Mechanisms of Resistance to Cancer Immunotherapy

Sitong Zhao

Department of Biochemical Engineering, INSA, Université de Toulouse, Toulouse 31013, France

Keywords: T Cells, Immune Checkpoint Blockade, Tumor Microenvironment, Gut Microbiome, Immunotherapy,

Resistance Mechanisms.

Abstract: Cancer immunotherapy has taken center stage in recent years as it can elicit a long-lasting anti-cancer

response. However, the response rates are not consistently high in every patient. The majority of cancers still

develop resistance to immunotherapy ranging from tumor intrinsic, microenvironment associated or host-

related pathways. These include aberrant neoantigen presentation/processing, over-activation of tumor-cell-

intrinsic signaling pathways, aberrant epigenetic regulation, presence of immunosuppressive cells, cytokines

and chemokines, overexpression of multiple immune checkpoints and composition of gut bacteria. This

review will focus on understanding the resistance mechanisms to immunotherapy in cancer and discuss ways

to overcome this.

1 INTRODUCTION

Cancer immunotherapy utilizes or reactivates the

patient's immune system, especially their T cells, to

kill cancer cells. Meanwhile, it exerts a long-lasting

anti-cancer response on the human body, which is

unmatched compared to other therapies (Ribas &

Wolchok, 2018). As evidence shows, blocking PD-

1/PD-L1 or CTLA-4 pathways can induce long-

lasting remission of cancers including melanoma,

urothelial cancer, head and neck squamous cell

carcinoma (HNSCC), lung cancer and renal cell

carcinoma (RCC). These therapies have also obtained

FDA approvals (Gong et al., 2018). Additional to the

PD-1/PD-L1/CTLA-4 immunotherapies, several

other targeted immunotherapy options range from

chimeric antigen receptor-modified T cells (CAR-T

cell) therapy, cancer vaccines, and oncolytic viruses,

which have shown positive results clinically and pre-

clinically. For example, the CAR-T cell therapy for B

cell malignancies has been proven effective and safe,

especially one of which targeting CD19 reached an

overall survival rate of 78% (Maude et al., 2014).

Although cancer immunotherapy has been widely

and rapidly applied to treat various types of cancer,

only a few patients (responders) have benefited from

them due to the complexity of immune systems.

Many patients do not produce any clinical benefit

(non-responders/ innate resistance) after

immunotherapy. For example, tumors that have

limited T cells in the tumor microenvironment

(TME), called immune cold or immune-desert

cancers such as prostate cancer, have had minimal

benefit from immunotherapy (Galon & Bruni, 2019;

Hegde et al., 2016). This form of innate resistance can

also be seen in glioblastoma and breast cancer, which

have low objective response rates with the anti- PD-

1/PD-L1 therapy (Dirix et al., 2018; Hansen et al.,

2018; Lukas et al., 2018). Additionally, some patients

first respond to immunotherapy but subsequently

develop acquired resistance (Jenkins et al., 2018).

Therefore, it is vitally important to determine the

mechanism through which cancers regulate

immunotherapy resistance.

The resistance mechanisms to cancer

immunotherapy are divided into three parts, tumor-

cell-intrinsic mechanism, TME-related mechanism,

and host-related mechanism. The tumor-cell-intrinsic

mechanism includes the alteration of neoantigen,

tumor cell signaling pathway and epigenetic

regulation. The TME-related mechanism involves

immunosuppressive cells, cytokines, chemokines and

multiple immune regulators. Finally, the host-related

mechanism is associated with patients' gender, age

and gut bacteria. This review will concentrate on the

mechanisms of resistance to cancer immunotherapy

352

Zhao, S.

Mechanisms of Resistance to Cancer Immunotherapy.

DOI: 10.5220/0012021000003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 352-369

ISBN: 978-989-758-637-8

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

from these three parts above and discuss ways to

overcome immunotherapy resistance.

2 TUMOR-CELL INTRINSIC

MECHANISM

2.1 Alteration of Neoantigen

Though cancers have been known to be infiltrated by

antigen-specific CD8+ cytotoxic immune cells, they

often do not elicit an immune response. The ability of

cancers to initiate an adaptive immune response

depends on the presentation of neoantigenic peptides

by the cancer cell and their subsequent recognition by

cytotoxic cells (Reeves & James, 2017; Snyder et al.,

2014). A high tumor mutational burden (TMB),

denoted by increased mutations within a cancer cell,

usually accompanies the production of increased

neoantigens by cancer (Hugo et al., 2017; Perumal et

al., 2020; Rizvi et al., 2015; Schumacher & Schreiber,

2015). This indicates higher immunogenicity within

the tumor and immunotherapy targeting these tumors

have produced a favorable response. However,

cancers have the ability to alter the expression of and

presentation of neoantigens to aid in immune escape

(Veldman et al., 2020) (Figure 1).

High TMB cancers such as non-small cell lung

cancer (NSCLC) and melanoma produce increased

neoantigens, resulting in a favorable response to anti-

PD-1/PD-L1 therapy (Goodman et al., 2017b). By

contrast, tumors such as prostate cancer with low

TMB, which lack neoantigens, are less sensitive to

immunotherapy (Schumacher & Schreiber, 2015).

Additionally, Hellmann et al. found that high TMB

positively correlated to an immunotherapy response,

durable benefit, and progression-free survival with

immune checkpoint blockade treatment (Hellmann et

al., 2018). However, several studies have pointed out

that the clinical efficacy of immunotherapy does not

strongly depend on high TMB alone (Goodman et al.,

2017a; Gromeier et al., 2021; Strickler et al., 2021).

For example, patients with glioblastoma, a low TMB

cancer, had favorable survival responses to

immunotherapy (Gromeier et al., 2021).

Studies have also found that epigenetic changes

resulting in loss of neoantigen expression can aid

cancers to evade immune surveillance (De Vries et

al., 1997). For example, hypermethylation of the

promoter of neoantigen expressing genes during

transcription resulted in neoantigen silencing

(Rosenthal et al., 2020).

Abnormal antigen processing can lead to errors in

antigen presentation, impairing cytotoxic CD8+ T

cells to recognize the antigen, leading to immune

escape. In general, neoantigenic peptides are

processed into antigenic peptides by the proteasome

together with low molecular mass proteins (LMP).

Processed peptides are transported into the

endoplasmic reticulum (ER) via the transporter

associated with antigen processing proteins (TAP)

and assembled with human leukocyte antigen (HLA)

and Beta-2-Microglobulin (B2M) to form the major

histocompatibility complex class 1 (MHC-1). These

complexes are then transported on the tumor cell

surface, which aids in T cell recognition (SELIGER

et al., 1997). Naturally, all of these steps are

indispensable for the presentation of neoantigens. In

cancer patients, loss and down-regulation of LMP2,

LMP7 and TAP1 were reported, resulting in the

failure of presentation of neoantigens (Meissner et al.,

2005). The expression rates of LMP2, LMP7, TAP1,

TAP2, and HLA were also found to predict the overall

survival of cancer immunotherapy (Meissner et al.,

2005). Studies have found that loss of heterozygosity

and loss of function of the HLA gene, which is one of

the mechanisms causing immune evasion

(Mcgranahan et al., 2017). After treatment with an

RNA mutanome vaccine, B2M-deficient patients

with melanoma lacking presentation of neoantigens

had increased tumor growth, leading to recurrence,

indicating that this is also one of the resistance

mechanisms to immunotherapy (Sahin et al., 2017).

Tumor cell division can produce new mutant

subclones leading to intratumoral heterogeneity. The

selective pressure by immune sculpting can result in

the expansion of subclones that lack neoantigens or

down-regulate their genes in presentation machinery,

aiding cancer growth and reducing the effect of

immunotherapy (Mcgranahan et al., 2016).

Mechanisms of Resistance to Cancer Immunotherapy

353

Figure 1: Neoantigen-related mechanism of resistance to immunotherapy.

Tumor mutation generates tumor-specific

peptides or neo-antigenic peptides. Peptides produced

are processed into antigenic peptides by the

proteasome where the LMP is involved. Next, the

antigenic peptides are transported into the ER, where

they are loaded onto the MHC class 1 complex which

consists of HLA-A, B, C and B2M. Finally, MHC is

transported and displayed on the tumor cell surface

and recognized by the TCR of T cells. Lack of

neoantigen due to low TMB, loss of neoantigen due

to the silencing of neoantigen (such as methylation)

and disruption in antigen presentation machinery

(such as the abnormal expression of LMP, TAP, HLA

and B2M) can result in immunotherapy resistance.

2.2 Epigenetic Regulation of Antigen

Presentation and Recognition

Pathway

Aberrant epigenetic regulation has been reported to

mediate various tumor-related genes, induce tumor

progression and metastasis and promote

immunotherapy resistance (Baylin & Jones, 2016;

Maio et al., 2015). Epigenetic regulation can also

suppress the expression and presentation of tumor-

associated antigens through processes like DNA

methylation, acetylation and histone modification

(Cao & Yan, 2020). In tumors resistant to

immunotherapy, down-regulation of immunogenic

antigens through DNA methylation has been reported

and DNA demethylating agents could restore the

expression of neoantigens (Wylie et al., 2019). As

mentioned above, HLA, TAP and B2M are involved

in the antigen presentation machinery. The promoter

region of the HLA gene has been reported to be

methylated, inhibiting its expression and resulting in

an impaired CD8+ T cell response (Luo et al., 2018).

Methylation was also observed in the promoter region

of B2M (Snahnicanova et al., 2020). Similarly,

reduced recruitment of histone acetyltransferase to

TAP-1 promoter regions was linked to its reduced

transcription, leading to dysfunctional antigen

presentation (Setiadi et al., 2007). This imbalance in

proteins involved in antigen presentation via

epigenetic regulations can result in a lack of

immunogenic antigens, resulting in resistance to

immunotherapy.

The function of T cells is also regulated by

epigenetic modification. For instance, PD-1, CTLA-

4, lymphocyte-activation gene 3 (LAG-3), and T cell

immunoglobulin domain and mucin domain 3 (TIM-

3), were demethylated or hypomethylated leading to

T-cell exhaustion (Sasidharan Nair et al., 2018).

Furthermore, the enhancer of zeste homologue 2

(EZH2) induced H3 trimethylation and DNA

methyltransferase 1 (DNMT1) induced DNA

methylation, leading to a decrease in the expression

of chemokines CXCL9 and CXCL10, important for T

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354

helper cell recruitment into the tumor stroma

(Nagarsheth et al., 2016; D. Peng et al., 2015).

Cancer cells also have the ability to prevent T cell-

induced apoptosis by regulating cell-extrinsic

apoptotic pathways through epigenetic regulation.

The binding of Fas-L on the CD8+ lymphocytes with

its counterpart FAS on the tumor cell can trigger

apoptosis of the cancer cell. However, cancers can

downregulate the expression of Fas and TRAIL-R1

proteins by DNA methylation, preventing CD8+

induced apoptosis (Hopkins-Donaldson et al., 2003).

Similarly, histone deacetylation has also been

implicated in silencing TRAIL and Fas signaling

pathways (Insinga et al., 2005).

Epigenetic induced immunotherapy resistance

can be overcome by combining immunotherapy with

drugs targeting epigenetic modifications, and this

combination has produced favorable outcomes in

recent clinical trials (Gallagher et al., 2017; Pauken et

al., 2016). For example, histone deacetylase inhibitor

(HDACi) can overcome the resistance to monoclonal

anti-CD52 antibody (alemtuzumab) in patients with

T-cell prolymphocytic leukemia (Hasanali et al.,

2015). Likewise, DNA hypomethylating agents

(DHAs) guadecitabine combined with anti-CTLA-4

antibody ipilimumab displayed promising tumor

immunomodulation through the upregulation of HLA

class I and increasing CD8+, PD-1+ T cells and

CD20+ B cells in a phase Ib trial (Di Giacomo et al.,

2019).

2.3 Tumor-Intrinsic Cell Signaling

Pathway

Studies have shown that the alteration of various

oncogenic cell signaling pathways can affect the

immune response to tumors (Aldea et al., 2021;

Kalbasi & Ribas, 2020). The changes may affect the

expression of transcription factors, resulting in

aberrant antigen presentation, expression of immune

checkpoint-related proteins, or the production of

immunosuppressive cytokines (Fares et al., 2019; W.

Peng et al., 2016). It is also vital to note that the role

of the tumor cell signaling pathway will have a

context-dependent role in promoting

immunosuppression.

2.3.1 Alteration of PI3k/AKT Signaling

Pathway

The PI3K/AKT signaling network is activated via

ligand binding to receptor tyrosine kinases (RTK), G

protein-coupled receptors (GPCR), or cytokine

receptors. This pathway plays a central role in

promoting cell survival and growth (Hoxhaj &

Manning, 2020). The proteins phosphatidyl-inositol-

3-kinases (PI3Ks), protein kinase B (AKT),

mammalian target of rapamycin (mTOR) and

phosphatase and tensin homolog (PTEN) are

involved in this signaling network. PTEN is the

negative regulator of PI3k/AKT signaling netwpork,

which inhibits PI3K and prevents AKT activation

(Porta et al., 2014). Thus, loss of PTEN induces

abnormally activation of the PI3k/AKT signaling

pathway (Porta et al., 2014).

The expression of PD-L1, one of the immune

checkpoint inhibitory receptors, has been reported to

be controlled by the PI3K-AKT-mTOR pathway.

Membranous expression of PD-L1 is positively

correlated with the activation of mTOR, thereby

reducing tumor-infiltrating T cells, increasing

regulatory T cells (Tregs), and resulting in immune

escape (Lastwika et al., 2016). Loss of PTEN has

been shown to up-regulate immunosuppressive

cytokines of CCL2 and VEGF, which can recruit

tumor-associated macrophages (TAMs) and aid in

immune escape (W. Peng et al., 2016; Voron et al.,

2014; H. Yang et al., 2020). Additionally, increased

VEGF can also cause abnormal angiogenesis. This

potentiates the immunosuppressive phenotype by

recruiting suppressive immune cells, such as Tregs

and myeloid-derived suppressor cells (MDSCs),

reported to promote resistance to immunotherapy in

melanoma (W. Peng et al., 2016; Voron et al., 2014).

Mutations in PIK3CA coding the p110 subunit of

PI3K cause abnormal activation of the PI3K and can

reduce immune infiltration (Borcoman et al., 2019;

Madsen et al., 2018). Direct activation of the PI3k-

AKT pathway through activating mutations can also

lead to a suppressive tumor microenvironment. For

example, RHOA mutations in gastric cancer (GC) can

trigger the PI3K-AKT-mTOR pathway to increase

the synthesis of free fatty acids (released by tumor

cells), which promotes Treg cell metabolism,

ultimately contributing to an increased Tregs in TME

(Kumagai et al., 2020).

2.3.2 Alteration of ERK/MAPK Signaling

Pathway

Similar to PI3K/AKT signaling pathway, mitogen-

activated protein kinase (MAPK) signaling is

activated when receptors such as RTKs and GPCRs

bind to their ligand. Hyperactivation of this pathway

results in cancer development and progression. The

main proteins involved in this signaling pathway are

RAS, RAF, MEK and ERK from upstream to

downstream (Guo et al., 2020).

Mechanisms of Resistance to Cancer Immunotherapy

355

The expression of PD-L1 can be regulated by

ERK/MAPK signaling pathway, and the activation of

this pathway can also decrease the TILs (Loi et al.,

2016; Sumimoto et al., 2016). Abnormal EGFR

signaling via the MAPK pathway can up-regulate the

expression of PD-L1 through the p-ERK1/2/p-c-Jun

transcription factors, causing T cell apoptosis (Chen

et al., 2015). The activation of RAS and its

downstream signaling MEK can also indirectly

promote PD-L1 expression by inhibiting AU-rich

element-binding protein tristetraprolin (TTP) by

kinase MK2 (Coelho et al., 2017). KRAS (one of RAS

family members) mutation mediates the inhibition of

interferon regulatory factor 2 (IRF2), leading to high

expression of CXCL3 to form an immunosuppressive

microenvironment (Liao et al., 2019). Furthermore,

the eukaryotic translation initiation complex (eIF4F)

located downstream of the PI3K-AKT and ERK-

MAPK pathway regulates PD-L1 transcriptional

factor STAT1, whose activation has a positive

correlation with the activation of PD-L1 (Cerezo et

al., 2018). Clinically, in patients who developed

hyperprogressive disease following anti-PD-1

therapy, it was found to have over activation of the

ERK/MAPK, PI3K/AKT, IGF-1 and TGF-b

signaling pathways, suggesting their role in

promoting immunotherapy acquired resistance

(Xiong et al., 2018).

2.3.3 Alteration of Wnt/β-Catenin Signaling

Pathway

Wnt/β-Catenin signaling pathway is activated upon

Wnt ligand binding to Frizzled receptors. As a result,

β-Catenin translocates into the nucleus and binds to

transcription factors of target genes related to cancer

progression (Zhang & Wang, 2020).

Studies have shown that the Wnt/β-catenin

pathway may promote immunotherapy resistance by

producing immunosuppressive cytokine IL-10 in

melanoma (Yaguchi et al., 2012). Melanoma cells

expressing β-catenin cannot produce C-C motif

chemokine ligand (CCL4), causing defective

recruitment of antigen-presenting CD103+ Dendritic

Cells (DCs). This can lead to the loss of the

chemokines derived by CD103+ DCs, such as CXC

motif chemokine ligand 9 (CXCL9) and CXCL10,

which reduce cytotoxic T lymphocytes (CTLs) tumor

infiltration and damage the anti-tumor immune

response (Spranger et al., 2015). Another example

also reported that in non-T-cell-inflamed tumors, the

activation of tumor-intrinsic WNT/β-catenin

signaling reduced immune cell infiltration (Luke et

al., 2019).

2.3.4 Alteration of Cell Signaling Pathways

Related to IFN

Tumor intrinsic interferon (IFN) signaling pathway is

activated via autocrine and paracrine IFNs binding

onto its receptor (IFNGR1/IFNGR2) (Dunn et al.,

2006; Reisländer et al., 2019). This mediates the

transcription of interferon-stimulated genes through

the JAK-STAT pathway, resulting in enhanced T cell

response and the tumor cells' apoptosis (Ni & Lu,

2018; Reisländer et al., 2019). However, contrary to

this, the IFN pathway has also been implicated in

resistance to immunotherapy.

One mechanism of acquired resistance to anti-PD-

1 immunotherapy has been linked to the mutation of

JAK1/2. This mutation prevents activation of

downstream IFN transcription factor, which impairs

the transcription of interferon receptors, resulting in

the lack of IFN receptors and decreasing the effect of

IFN (Zaretsky et al., 2016). JAK1/2 loss of function

mutation has also been shown to inhibit the

expression of PD-L1 and the response to anti-PD-L1

therapy (Shin et al., 2017). Mutations of IFN-γ

pathway genes, such as IFNGR1, IFNGR2, IRF-1 and

JAK2, also resulted in unfavorable responses to anti-

CTLA-4 therapy, which could be a mechanism of

resistance to immunotherapy (Gao et al., 2016).

Interestingly, anti-CTLA-4 therapy can increase the

interferon-γ response genes, including CTLA-4

through the JAK-STAT pathway, resulting in

resistance to CTLA-4 (Mo et al., 2018). It is also

shown that IFN-γ promoted PD-L1 expression

resulting in immune evasion via the cell signaling

pathway of JAK-STAT -IRF1 (Garcia-Diaz et al.,

2017).

3 TUMOR-CELL EXTRINSIC

MECHANISM

3.1 Immune Contexture of the Tumor

Microenvironment

In addition to tumor-intrinsic resistance mechanisms,

tumor TME also plays a vital role in causing

resistance to cancer immunotherapy. The TME

includes immunosuppressive cells, cytokines and

chemokines, which could impair cytotoxic cells and

the immune system (Galon & Bruni, 2019; Hegde et

al., 2016). Additionally, some tumors have been

reported to reduce the presence of T cells in the

microenvironment, such as prostate cancer (Galon &

Bruni, 2019; Hegde et al., 2016). The immune cell

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356

composition within the tumor is also an essential

factor that could predict response to immunotherapy.

The TME consists of cytotoxic cells such as CD8+

T cells, NK cells and DC cells that aid immune

surveillance and cancer destruction. However, it also

contains MDSCs, Tregs and M2 macrophages, which

are immunosuppressive and induce immune system

dysfunction and tumor immune escape, resulting in

resistance to cancer immunotherapy (Aldea et al.,

2021). In the TME, MDSCs are able to inhibit the

proliferation and activity of CD8+ T cells and release

immunosuppressive cytokines, promoting tumor

proliferation and metastasis (Hou et al., 2020; Law et

al., 2020). Tregs are immunosuppressive to aid

immune homeostasis, but in tumors, they promote

tumor progression as a suppressor of anti-tumor

immunity via releasing immunosuppressive

cytokines and binding to tumor cells or antigen-

presenting cells (APCs), leading to T-cell exhaustion

(Takeuchi & Nishikawa, 2016). Unlike the above

two, Macrophages have a high degree of plasticity,

which have been classified as M1 and M2 (Mosser &

Edwards, 2008). M1 macrophages are involved in

anti-tumor immunity, while M2 macrophages (also

known as tumor-associated macrophages, TAMs) are

related to the progression and metastasis of tumors

and the formation of immunosuppressive TME

(Italiani & Boraschi, 2014). And its

immunosuppressive function is similar to MDSCs

(Italiani & Boraschi, 2014).

In the clinic, MDSCs, Tregs and TAMs frequency

were shown to be related to unfavorable prognosis

and shorter overall survival (OS) in various types of

cancer (Ai et al., 2018; Fridman et al., 2012). For

example, patients developing resistance to anti-PD-1

therapy showed an increased expression of TIM-3

binding to galectin-9 on MDSCs when the treatment

failed (Limagne et al., 2019).

Recently, there has been an influx in treatments

targeting the composition of the immune

microenvironment to prevent innate resistance to

immunotherapy. Combination treatment with CTLA-

4 and PD-L1 inhibitors has been reported to increase

T cell infiltration in immune cold prostate cancer

(Sharma et al., 2020). As mentioned above, TAMs

can also promote tumor angiogenesis. Treatment with

bispecific anti-ANG2/VEGF-A antibody (CrossMab,

A2V) successfully improved the survival rate of

vasculature-aberrant glioblastoma, owing to the

reprogramming of TAMs from M2 to M1 (Kloepper

et al., 2016). With the treatment of CD25-blocking

monoclonal antibody daclizumab, Tregs lost the

immunosuppressive function and restored the ability

to generate interferon-γ (Rech et al., 2012).

3.2 Expression of Immune-Modulatory

Factors

MDSCs, TAMs and Tregs are able to release

cytokines within the TME, promoting tumor immune

evasion (Haist et al., 2021). MDSCs can secrete

interleukin-10 (IL-10), IL-17 and transforming

growth factor-β (TGF-β). TAMs can also secrete

TGF-β and IL-10. This results in suppressing CD8+

T-cell function and promotes the immunosuppressive

function of Tregs (Huang et al., 2006; Wang et al.,

2019; Z. Yang et al., 2010). The proliferation and the

function of T cells can be inhibited by Tregs via

secreting cytokines, such as IL-35, IL-10 and TGF-β

(Jarnicki et al., 2006; Turnis et al., 2016). IL-35 can

also promote multiple inhibitory receptors such as

PD1, TIM-3, LAG-3 and cause T cell exhaustion

(Turnis et al., 2016). Besides T cells, NK cells are also

inhibited by the MDSCs secreting TGF-β1 (Li et al.,

2009). TGF-β1, secreted by MDSCs, TAMs and

Tregs, can also contribute to adaptive immunotherapy

resistance to anti-PD1 therapy by restricting T cell

infiltration (Mariathasan et al., 2018). Treatments co-

targeting these chemokines with immunotherapy

agents can prevent resistance and have shown clinical

benefits. A combination of anti-CXCR2 (CXCR2

expressing by MDSCs) with anti-PD1 was shown to

reduce tumor size and enhance T-cell infiltration

(Najjar et al., 2017). The bifunctional agent (anti-PD-

L1 and anti-TGFβ), Bintrafusp Alfa, enhanced tumor

cell lysis and reduced Tregs activity (Lind et al.,

2020).

3.3 Multiple Inhibitory Regulators

Immune checkpoints can regulate the activation of

CD8+ T cells, of which the most common ones are

PD-1 and CTLA-4. In addition to the two, there are

more inhibitory regulators which can bind to the

surface of tumor cells or APCs, leading to T-cell

exhaustion. These include LAG-3, TIM-3, T cell

immunoreceptor with Ig and ITIM domain (TIGIT),

and V-type immunoglobulin domain-containing

suppressor of T cell activation (VISTA) (Ding et al.,

2020; Kurachi, 2019). Immune checkpoint treatments

have shown to up-regulate secondary immune

regulators that cause immunotherapy resistance

(Nowicki et al., 2018). Therefore, the combination

treatment with multiple immune regulators can

enhance the effect of checkpoint blockade

monotherapy (Long et al., 2018; Seidel et al., 2018).

For example, the patients that showed no response to

monotherapy of ipilimumab (anti-CTLA-4) benefited

from a subsequent therapy of nivolumab (anti-PD-1)

Mechanisms of Resistance to Cancer Immunotherapy

357

in melanoma (Weber et al., 2013). There was also the

case when combining an anti-PD-L1 agent with an

anti-Tim-3 agent. Combination treatment reversed T

cell exhaustion and reduced the tumor growth in

colon carcinoma (Sakuishi et al., 2010). Combining

multiple checkpoint inhibitors could be a promising

strategy to overcome immunotherapy resistance.

3.4 Tumor Cell-Extrinsic Metabolic

Pathway

The metabolic pathway around the TME also plays a

vital role in promoting resistance to immunotherapy.

It includes the pathway of glycolysis, the pathway of

depleting various amino acids, and the production of

adenosine. Cancer cells and surrounding immune

cells undergo these metabolic reprogramming that

can promote resistance to immunotherapy (Fares et

al., 2019).

In 1926, Warburg proposed that tumor cells obtain

energy through tumor-specific glycolysis, producing

a large amount of lactic acid (Warburg, 1956;

Warburg et al., 1927). Aberrant glycolysis results in

the production of lactate and H

, which are released

by various H

transporters (such as monocarboxylate

transporter 4, MCT4) into the extracellular matrix.

This results in a lower extracellular pH (pH

) and

tumor acidosis (Corbet & Feron, 2017). Warburg

effect in cancer cells can influence the immune

response of immunotherapy partly via glucose

competition, lactate production, and the creation of an

acidic TME.

Studies have shown a glucose competition

between tumor cells and T cells, which restricts T cell

function by reducing their glycolytic capacity,

cytolytic activity, cytokines production and IFN-γ

production. This leads to T cell hyporesponsiveness

and an impaired immune response (Cham et al., 2008;

Chang et al., 2015). However, recent findings have

suggested that MDSCs and TAMs have the highest

glycolytic capacity, outcompeting the T cells for

glucose over the cancer cells (Reinfeld et al., 2021).

The resulting lactate produced from glycolysis was

also shown to decrease the cytotoxic activity and the

expression of granzyme and perforin in NK cells,

suppressing their anti-tumor immune response

(Husain et al., 2013). Additionally, a lower pH

TME causes the reduction of cytotoxic cytokines,

such as tumor necrosis factor-alpha (TNF-α) and

interferon-gamma (INF-γ) (Müller et al., 2000). This

acidic condition has also been reported to promote

macrophage polarization towards an

immunosuppressive phenotype, TAM (Bohn et al.,

2018).

Within the TME, there is also competition for the

consumption of amino acids, such as tryptophan,

cysteine, and arginine by the immunosuppressive

cells. MDSCs can reduce the level of local tryptophan

by expressing indoleamine 2,3 dioxygenase (IDO),

causing the reduction of nutrients for T cells leading

to their dysfunction (Yu et al., 2013). In murine

models, the combination therapy of checkpoint

inhibitors with IDO blockade can reactivate these

dysfunctional T cells and restore their IL-2

production (Spranger et al., 2014). Additionally,

MDSCs are also known to sequester essential amino

acid cystine and reduce the availability of cysteine

within the TME. Reduction in free cysteine can

downregulate T cell activation as T cells cannot

produce cysteine due to lack of cystathionase

(GMÜNDER et al., 1991; Srivastava et al., 2010). L-

arginine, which regulates the T-cell cycle

progression, can also be depleted by MDSCs and

TAMs through arginase I, further contributing to

immunotherapy resistance (Barbul & Dawson, 2018;

Munder et al., 2006; Rodriguez et al., 2007).

CD39 and CD73 are known to convert free ATP

into adenosine which is released into the TME and

can inhibit T cell function via its interaction with A2A

receptors (A2AR) or A2B receptors (A2BR) on

immune cells. This results in immune suppression via

the increased expression of various immune

checkpoints and decreased cytokine production (B.

Allard et al., 2017; D. Allard et al., 2017; Cekic &

Linden, 2016; Sek et al., 2018). Extracellular

adenosine can promote CTLA-4 expression in Tregs

and reduce IL-7 levels, which aids in the development

and survival of naïve T cells (Cekic et al., 2013;

Deaglio et al., 2007). The activation of A2BR can also

promote the expansion of MDSCs (Ryzhov et al.,

2011). Preclinically, it has shown that combinations

of checkpoint inhibitors with A2AR blockade can

inhibit adenosine and restore T cell function, and the

combination with CD73 blockade can reduce the

conversion of adenosine. Targeting the metabolic

pathways in cancer can be a potential therapeutic

strategy to overcome resistance to immunotherapy

(B. Allard et al., 2013; Beavis et al., 2015).

4 HOST-RELATED MECHANISM

OF RESISTANCE

Host-associated factors such as age, gender, and

composition of intestinal bacteria may also affect the

response to immunotherapy (Figure 2). It had been

previously reported that aging could dampen the

ICBB 2022 - International Conference on Biotechnology and Biomedicine

358

function of the immune system, thereby affecting the

efficacy of immunotherapy (Hong et al., 2019).

However, a recent meta-analysis indicated no

association between age and the effectiveness of

immunotherapy (F. Yang et al., 2020). Similarly,

several studies have also shown opposing results

regarding the association between the efficacy of

immunotherapy and gender (Wallis et al., 2019; F.

Yang et al., 2020).

There is growing evidence suggesting that the

host-microbiome has a role in modulating response to

cancer immunotherapy. It was reported that the

pathogen-associated molecular patterns (PAMPs)

from the intestinal microbiome, such as

lipopolysaccharide, could directly activate APCs

such as DCs, which can translocate into mesentery

lymph nodes (MLNs) to prime the B and T cells at

distant sites (Stary et al., 2015). Additionally, the gut

microbiomes are able to induce the secretion of

immunomodulatory factors to regulate the immune

system. For example, short-chain fatty acids (SCFAs)

(such as pentanoate and butyrate) are microbial

metabolites, which can increase cytokine production,

such as TNF-α, CD25 and IFN-γ to enhance the anti-

tumor function of T cells and CAR-T therapy (Luu et

al., 2021). In germ-free (GF) mice, tumor progression

was not controlled by anti-CTLA-4 therapy, while the

GF mice fed with B. uniformis restored the

responsiveness to anti-CTLA-4 therapy (Vétizou et

al., 2015). As a result, the combination of

immunotherapy and gut microbiome seems to be a

promising strategy to overcome the resistance in the

clinic. The treatment with Bifidobacterium can

enhance anti-PD-L1 therapy in vivo, resulting in

abolishing the growth of tumors via increasing

expression of the genes involved in CD8+ T cell

activation, antigen processing and presentation, and

interferon signaling (Sivan et al., 2015). Furthermore,

a higher microbial diversity with Bifidobacterium

longum, Collinsella aerofaciens, Enterococcus

faecium, Ruminococcaceae, Clostridiales, and

Faecalibacterium is also associated with a better

prognosis for checkpoint blockade therapy

(Gopalakrishnan et al., 2018; Matson et al., 2018).

Figure 2: Host-related mechanism of resistance to cancer immunotherapy.

The association between age or gender and effects

on immunotherapy response is controversial. The

gut microbiome can activate PAMPs, which in turn

recruits APCs to prime T and B cells. The

composition of the gut microbiome is vital in

influencing immunotherapy response. Gut microbiota

has also been reported to up-regulate the production

of TNF-α, CD25 and IFN-γ, which can enhance the

effect of cancer immunotherapy.

Mechanisms of Resistance to Cancer Immunotherapy

359

5 DISCUSSION AND

CONCLUSION

In this review, we have identified multiple

mechanisms of immunotherapy resistance and

potential areas for future research. Resistance to

immunotherapy emerges from a complex list of

factors which are tumor-cell intrinsic, extrinsic

(Figure 3) or host-related. Research into patient

stratification for immunotherapy and identifying

resistance biomarkers are both essential in ensuring

better treatment responses. With the emergence of

various immunotherapy resistances, combination

treatments with other targeted therapies have

gradually entered the clinical stage. The main aim of

this combination treatment is to use targeted therapies

to block immunotherapy resistance mechanisms such

as tumor intrinsic and extrinsic pathways mentioned

in this review. The combination of CTLA-4 and PD-

1 blockers has achieved great success in the clinic,

lessening the resistance to the monotherapy in

multiple types of cancer (Rotte, 2019). Similarly,

indoximod was added to the treatment of

pembrolizumab to overcome the resistance from the

up-regulated expression of IDO (Zakharia et al.,

2021). Combination of DNA hypomethylating agent

(DHA) guadecitabine with anti-CTLA-4 antibody

ipilimumab resulted in increased CD8+ infiltration

and prevented resistance induced from HLA class I

downregulation (Di Giacomo et al., 2019). Likewise,

the pan-PI3K inhibitor copanlisib enhanced the effect

of the monotherapy of immune checkpoint inhibitors

(Yan et al., 2021). Identifying combination treatments

that can improve the primary immunotherapy

response and block immunotherapy resistance

mechanisms is an important strategy needed to

achieve better treatment results. Table 1 lists clinical

trials of current combination therapy programs.

Table 1: List of combination therapy against the resistance to cancer immunotherapy.

Resistance Mechanism

Clinical Trial

Cancer Type Cancer Characterization Combination Therapy Agents

Targets

(respectively)

Phase

Neoantigen

Lack of

neoantigen

NCT03827044 Colon cancer Stage III 5-FU + Avelumab

Chemotherapy

and PD-L1

Phase 3

NCT04397003

Small cell lung

cancer

Extensive stage Neoantigen DNA vaccine + Durvalumab

Neoantigen and

PD-L1

Phase 2

NCT03867175 Lung cancer Metastatic or stage IV

Stereotactic Body Radiation +

Pembrolizumab

Radiation

therapy and PD-1

Phase 3

Alteration of cell

intrinsic signaling

pathway

PI3K/AKT

signaling

pathway

NCT03257722

Non-small cell

lung cancer

Metastasic or Recurrent Idelalisib + Pembrolizumab PI3K-δ and PD-1

Phase

1b/2

NCT03502733

Solid tumor or

lymphoma

Metastatic or Recurrent

or Unresectable or stage

III/ IV

Copanlisib + Ipilimumab + Nivolumab

PI3K and CTLA4

and PD-1

Phase 1b

NCT03190174

Sarcoma and

certain cancers

Advanced Nab-Rapamycin + Nivolumab mTOR and PD-1 Phase 1/2

ERK/MAPK

signaling

pathway

NCT01754376 Melanoma

Mutant in the BRAF

gene

Vemurafenib + Aldesleukin(IL-2)

BRAF and T

cells/NK cells

Phase 2

NCT04163237 Liver cancer Advanced Sorafenib + PD-1

ERK/MAPK

signaling

pathway + VEGFR

and PD-L1

Phase 3

NCT03363867

Ovarian &

Fallopian tube

cancer &

Peritoneal

carcinoma

Recurrent

Cobimetinib + Bevacizumab +

Atezolizumab

MEK and VEGF

and PD-L1

Phase 2

VEGF-related

signaling

pathway

NCT04715633

Colorectal

cancer

Microsatellite instability

high

Apatinib + Camrelizumab VEGFR2 and PD-1 Phase 2

NCT03517449

Endometrial

cancer

Advanced Lenvatinib + Pembrolizumab VEGFR and PD-1 Phase 3

NCT04356729 Melanoma

Stage III/ IV or

unresectable

Bevacizumab + Atezolizumab VEGF and PD-L1 Phase 2

NCT01950390 Melanoma

Stage III/ IV or

unresectable

Bevacizumab + Ipilimumab VEGF and CTLA4 Phase 2

HER-related

signaling

pathway

NCT04740918 Breast Cancer

Metastasic & HER-2+ &

PD-L1+

Trastuzumab + Atezolizumab HER-2 and PD-L1 Phase 3

NCT03082534

Head & Neck

Squamous Cell

Carcinoma

Metastasic or Recurrent Cetuximab + Pembrolizumab EGFR and PD-1 Phase 2

Epigenetic

regulation

Alteration of

epigenetic

regulation

NCT03765229 Melanoma - Entinostat + Pembrolizumab HDAC and PD-1 Phase 2

NCT02608437 Melanoma Metastasic SGI-110 + Ipilimumab

DNMT and CTLA-

Phase 1

ICBB 2022 - International Conference on Biotechnology and Biomedicine

360

Tumor

microenvironment

TAMs and

MDSCs

NCT02452424

Melanoma and

other solid

tumors

Advanced PLX3397 + Pembrolizumab CSF1R and PD-1 Phase 1/2

NCT02880371 Solid tumors Advanced ARRY-382 + Pembrolizumab CSF1R and PD-1

Phase

1b/2

Multiple

Inhibitory

Regulators

NCT03084471 Solid tumors Advanced Durvalumab + Tremelimumab PD-L1 and CTLA4 Phase 3

NCT03680508 Liver cancer

Primary or Advanced or

Unresectable adult

primary

Cobolimab + Dostarlimab TIM-3 and PD-1 Phase 2

NCT04370704 Melanoma Advanced

INCAGN02385 + INCAGN02390 +

INCMGA00012

LAG-3 and TIM-3

and PD-1

Phase 1/2

Lack of T/NK

Cells

NCT01629758 Solid tumors - Denenicokin(IL-21) + Nivolumab

T/NK cells and

PD-1

Phase 1

NCT02989714

Renal Cell

Carcinoma

Metastasic IL-2 + Nivolumab

T/NK cells and

PD-1

Phase 1/2

IDO NCT02752074 Melanoma

Unresectable or

metastatic

Epacadostat + Pembrolizumab IDO and PD-1 Phase 3

Host-related

Host

Microbiome

NCT04924374 Lung Cancer Advanced

Microbiota capsule +

Pembrolizumab/Nivolizumab/Atezolizumab

Gut microbiome

and PD-1

Not

Applicable

NCT03341143 Melanoma -

Fecal Microbiota Transplant +

Pembrolizumab

Gut microbiome

and PD-1

Phase 2

Immunotherapy treatment has been linked to

producing a durable anti-tumor response and using

combination therapy to prevent resistance

mechanisms can enhance this. Currently, new

strategies are being used to recruit patients to

immunotherapy trials, such as measuring their tumor-

infiltrating T cell counts, PD-L1 expression and MSI

status (Hegde & Chen, 2020). However, current

clinical practices still lack prediction biomarkers for

immunotherapy resistance. Research into better

companion diagnostic tools that can offer

personalized immunotherapy regimes or

combinations can provide a long-lasting response for

patients.

Figure 3: Tumor cell-intrinsic and TME-related mechanisms of resistance to cancer immunotherapy.

Mechanisms of Resistance to Cancer Immunotherapy

361

Tumor cell-intrinsic mechanism includes

resistance via aberrant neoantigen

presentation/processing, over activation of tumor-

cell-intrinsic signaling pathway and epigenetic

regulation. TME-related resistance mechanisms

include 1) increased infiltration of

immunosuppressive cells, 2) secretion of cytokines

and chemokines, 3) metabolism of glucose, amino

acids and adenosine, and 4) expression of multiple

inhibitory regulators, resulting in dysfunction of the

immune system.

REFERENCES

Ai, L., Mu, S., Wang, Y., Wang, H., Cai, L., Li, W., & Hu,

Y. (2018). Prognostic role of myeloid-derived

suppressor cells in cancers: a systematic review and

meta-analysis. BMC Cancer, 18(1), 1–9.

https://doi.org/10.1186/s12885-018-5086-y

Aldea, M., Andre, F., Marabelle, A., Dogan, S., Barlesi, F.,

& Soria, J. C. (2021). Overcoming resistance to tumor-

targeted and immune-targeted therapies. Cancer

Discovery, 11(4), 874–899.

https://doi.org/10.1158/2159-8290.CD-20-1638

Allard, B., Longhi, M. S., Robson, S. C., & Stagg, J.

(2017). The ectonucleotidases CD39 and CD73: Novel

checkpoint inhibitor targets. Immunological Reviews,

276(1), 121–144. https://doi.org/10.1111/imr.12528

Allard, B., Pommey, S., Smyth, M. J., & Stagg, J. (2013).

Targeting CD73 enhances the antitumor activity of

anti-PD-1 and anti-CTLA-4 mAbs. Clinical Cancer

Research, 19(20), 5626–5635.

https://doi.org/10.1158/1078-0432.CCR-13-0545

Allard, D., Turcotte, M., & Stagg, J. (2017). Targeting A2

adenosine receptors in cancer. Immunology and Cell

Biology, 95(4), 333–339.

https://doi.org/10.1038/icb.2017.8

Barbul, A., & Dawson, H. (2018). Arginine and immunity.

Diet Nutrition and Immunity, March, 199–216.

https://doi.org/10.1201/9781351071390

Baylin, S. B., & Jones, P. A. (2016). Epigenetic

determinants of cancer. Cold Spring Harbor

Perspectives in Biology, 8(9), 1–35.

https://doi.org/10.1101/cshperspect.a019505

Beavis, P. A., Milenkovski, N., Henderson, M. A., John, L.

B., Allard, B., Loi, S., Kershaw, M. H., Stagg, J., &

Darcy, P. K. (2015). Adenosine receptor 2A blockade

increases the efficacy of anti-PD-1 through enhanced

antitumor T-cell responses. Cancer Immunology

Research, 3(5), 506–517.

https://doi.org/10.1158/2326-6066.CIR-14-0211

Bohn, T., Rapp, S., Luther, N., Klein, M., Bruehl, T. J.,

Kojima, N., Aranda Lopez, P., Hahlbrock, J., Muth, S.,

Endo, S., Pektor, S., Brand, A., Renner, K., Popp, V.,

Gerlach, K., Vogel, D., Lueckel, C., Arnold-Schild, D.,

Pouyssegur, J., … Bopp, T. (2018). Tumor

immunoevasion via acidosis-dependent induction of

regulatory tumor-associated macrophages. Nature

Immunology, 19(12), 1319–1329.

https://doi.org/10.1038/s41590-018-0226-8

Borcoman, E., De La Rochere, P., Richer, W., Vacher, S.,

Chemlali, W., Krucker, C., Sirab, N., Radvanyi, F.,

Allory, Y., Pignot, G., Barry de Longchamps, N.,

Damotte, D., Meseure, D., Sedlik, C., Bieche, I., &

Piaggio, E. (2019). Inhibition of PI3K pathway

increases immune infiltrate in muscle-invasive bladder

cancer. OncoImmunology, 8(5), 1–17.

https://doi.org/10.1080/2162402X.2019.1581556

Cao, J., & Yan, Q. (2020). Cancer Epigenetics, Tumor

Immunity, and Immunotherapy. In Trends in Cancer

(Vol. 6, Issue 7, pp. 580–592). Cell Press.

https://doi.org/10.1016/j.trecan.2020.02.003

Cekic, C., & Linden, J. (2016). Purinergic regulation of the

immune system. Nature Reviews Immunology, 16(3),

177–192. https://doi.org/10.1038/nri.2016.4

Cekic, C., Sag, D., Day, Y. J., & Linden, J. (2013).

Extracellular adenosine regulates naive T cell

development and peripheral maintenance. Journal of

Experimental Medicine, 210(12), 2693–2706.

https://doi.org/10.1084/jem.20130249

Cerezo, M., Guemiri, R., Druillennec, S., Girault, I.,

Malka-Mahieu, H., Shen, S., Allard, D., Martineau, S.,

Welsch, C., Agoussi, S., Estrada, C., Adam, J.,

Libenciuc, C., Routier, E., Roy, S., Désaubry, L.,

Eggermont, A. M., Sonenberg, N., Scoazec, J. Y., …

Robert, C. (2018). Translational control of tumor

immune escape via the eIF4F–STAT1–PD-L1 axis in

melanoma. Nature Medicine, 24(12), 1877–1886.

https://doi.org/10.1038/s41591-018-0217-1

Cham, C. M., Driessens, G., O’Keefe, J. P., & Gajewski, T.

F. (2008). Glucose deprivation inhibits multiple key

gene expression events and effector functions in CD8+

T cells. European Journal of Immunology, 38(9),

2438–2450. https://doi.org/10.1002/eji.200838289

Chang, C. H., Qiu, J., O’Sullivan, D., Buck, M. D.,

Noguchi, T., Curtis, J. D., Chen, Q., Gindin, M., Gubin,

M. M., Van Der Windt, G. J. W., Tonc, E., Schreiber,

R. D., Pearce, E. J., & Pearce, E. L. (2015). Metabolic

Competition in the Tumor Microenvironment Is a

Driver of Cancer Progression. Cell, 162(6), 1229–

1241. https://doi.org/10.1016/j.cell.2015.08.016

Chen, N., Fang, W., Zhan, J., Hong, S., Tang, Y., Kang, S.,

Zhang, Y., He, X., Zhou, T., Qin, T., Huang, Y., Yi, X.,

& Zhang, L. (2015). Upregulation of PD-L1 by EGFR

activation mediates the immune escape in EGFR-

driven NSCLC: Implication for optional immune

targeted therapy for NSCLC patients with EGFR

mutation. Journal of Thoracic Oncology, 10(6), 910–

923. https://doi.org/10.1097/JTO.0000000000000500

Coelho, M. A., de Carné Trécesson, S., Rana, S., Zecchin,

D., Moore, C., Molina-Arcas, M., East, P., Spencer-

Dene, B., Nye, E., Barnouin, K., Snijders, A. P., Lai,

W. S., Blackshear, P. J., & Downward, J. (2017).

Oncogenic RAS Signaling Promotes Tumor

Immunoresistance by Stabilizing PD-L1 mRNA.

Immunity, 47(6), 1083-1099.e6.

https://doi.org/10.1016/j.immuni.2017.11.016

ICBB 2022 - International Conference on Biotechnology and Biomedicine

362

Corbet, C., & Feron, O. (2017). Tumour acidosis: From the

passenger to the driver’s seat. Nature Reviews Cancer,

17(10), 577–593. https://doi.org/10.1038/nrc.2017.77

De Vries, T. J., Fourkour, A., Wobbes, T., Verkroost, G.,

Ruiter, D. J., & Van Muijen, G. N. P. (1997).

Heterogeneous expression of immunotherapy

candidate proteins gp100, MART-1, and tyrosinase in

human melanoma cell lines and in human melanocytic

lesions. Cancer Research, 57(15), 3223–3229.

Deaglio, S., Dwyer, K. M., Gao, W., Friedman, D., Usheva,

A., Erat, A., Chen, J. F., Enjyoji, K., Linden, J., Oukka,

M., Kuchroo, V. K., Strom, T. B., & Robson, S. C.

(2007). Adenosine generation catalyzed by CD39 and

CD73 expressed on regulatory T cells mediates

immune suppression. Journal of Experimental

Medicine, 204(6), 1257–1265.

https://doi.org/10.1084/jem.20062512

Di Giacomo, A. M., Covre, A., Finotello, F., Rieder, D.,

Danielli, R., Sigalotti, L., Giannarelli, D., Petitprez, F.,

Lacroix, L., Valente, M., Cutaia, O., Fazio, C., Amato,

G., Lazzeri, A., Monterisi, S., Miracco, C., Coral, S.,

Anichini, A., Bock, C., … Maio, M. (2019).

Guadecitabine plus ipilimumab in unresectable

melanoma: The NIBIT-M4 clinical trial. Clinical

Cancer Research, 25(24), 7351–7362.

https://doi.org/10.1158/1078-0432.CCR-19-1335

Ding, Q. Q., Chauvin, J. M., & Zarour, H. M. (2020).

Targeting novel inhibitory receptors in cancer

immunotherapy. Seminars in Immunology,

49(December), 101436.

https://doi.org/10.1016/j.smim.2020.101436

Dirix, L. Y., Takacs, I., Jerusalem, G., Nikolinakos, P.,

Arkenau, H. T., Forero-Torres, A., Boccia, R.,

Lippman, M. E., Somer, R., Smakal, M., Emens, L. A.,

Hrinczenko, B., Edenfield, W., Gurtler, J., von

Heydebreck, A., Grote, H. J., Chin, K., & Hamilton, E.

P. (2018). Avelumab, an anti-PD-L1 antibody, in

patients with locally advanced or metastatic breast

cancer: A phase 1b JAVELIN solid tumor study. Breast

Cancer Research and Treatment, 167(3), 671–686.

https://doi.org/10.1007/s10549-017-4537-5

Dunn, G. P., Koebel, C. M., & Schreiber, R. D. (2006).

Interferons, immunity and cancer immunoediting. In

Nature Reviews Immunology (Vol. 6, Issue 11, pp.

836–848). Nat Rev Immunol.

https://doi.org/10.1038/nri1961

Fares, C. M., Van Allen, E. M., Drake, C. G., Allison, J. P.,

& Hu-Lieskovan, S. (2019). Mechanisms of Resistance

to Immune Checkpoint Blockade: Why Does

Checkpoint Inhibitor Immunotherapy Not Work for All

Patients? American Society of Clinical Oncology

Educational Book, 39, 147–164.

https://doi.org/10.1200/edbk_240837

Fridman, W. H., Pagès, F., Saut

s-Fridman, C., & Galon, J.

(2012). The immune contexture in human tumours:

Impact on clinical outcome. Nature Reviews Cancer,

12(4), 298–306. https://doi.org/10.1038/nrc3245

Gallagher, S. J., Shklovskaya, E., & Hersey, P. (2017).

Epigenetic modulation in cancer immunotherapy.

Current Opinion in Pharmacology, 35, 48–56.

https://doi.org/10.1016/j.coph.2017.05.006

Galon, J., & Bruni, D. (2019). Approaches to treat immune

hot, altered and cold tumours with combination

immunotherapies. Nature Reviews Drug Discovery,

18(3), 197–218. https://doi.org/10.1038/s41573-018-

0007-y

Gao, J., Shi, L. Z., Zhao, H., Chen, J., Xiong, L., He, Q.,

Chen, T., Roszik, J., Bernatchez, C., Woodman, S. E.,

Chen, P. L., Hwu, P., Allison, J. P., Futreal, A., Wargo,

J. A., & Sharma, P. (2016). Loss of IFN-γ Pathway

Genes in Tumor Cells as a Mechanism of Resistance to

Anti-CTLA-4 Therapy. Cell, 167(2), 397-404.e9.

https://doi.org/10.1016/j.cell.2016.08.069

Garcia-Diaz, A., Shin, D. S., Moreno, B. H., Saco, J.,

Escuin-Ordinas, H., Rodriguez, G. A., Zaretsky, J. M.,

Sun, L., Hugo, W., Wang, X., Parisi, G., Saus, C. P.,

Torrejon, D. Y., Graeber, T. G., Comin-Anduix, B.,

Hu-Lieskovan, S., Damoiseaux, R., Lo, R. S., & Ribas,

A. (2017). Interferon Receptor Signaling Pathways

Regulating PD-L1 and PD-L2 Expression. Cell

Reports, 19(6), 1189–1201.

https://doi.org/10.1016/j.celrep.2017.04.031

GMÜNDER, H., ECK, H. ‐P, & DRÖGE, W. (1991). Low

membrane transport activity for cystine in resting and

mitogenically stimulated human lymphocyte

preparations and human T cell clones. European

Journal of Biochemistry, 201(1), 113–117.

https://doi.org/10.1111/j.1432-1033.1991.tb16263.x

Gong, J., Chehrazi-Raffle, A., Reddi, S., & Salgia, R.

(2018). Development of PD-1 and PD-L1 inhibitors as

a form of cancer immunotherapy: A comprehensive

review of registration trials and future considerations.

In Journal for ImmunoTherapy of Cancer (Vol. 6, Issue

1). BioMed Central Ltd.

https://doi.org/10.1186/s40425-018-0316-z

Goodman, A. M., Kato, S., Bazhenova, L., Patel, S. P.,

Frampton, G. M., Miller, V., Stephens, P. J., Daniels,

G. A., & Kurzrock, R. (2017a). Tumor mutational

burden as an independent predictor of response to

immunotherapy in diverse cancers. Molecular Cancer

Therapeutics, 16(11), 2598–2608.

https://doi.org/10.1158/1535-7163.MCT-17-0386

Goodman, A. M., Kato, S., Bazhenova, L., Patel, S. P.,

Frampton, G. M., Miller, V., Stephens, P. J., Daniels,

G. A., & Kurzrock, R. (2017b). Tumor mutational

burden as an independent predictor of response to

immunotherapy in diverse cancers. Molecular Cancer

Therapeutics, 16(11), 2598–2608.

https://doi.org/10.1158/1535-7163.MCT-17-0386

Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A.,

Andrews, M. C., Karpinets, T. V., Prieto, P. A.,

Vicente, D., Hoffman, K., Wei, S. C., Cogdill, A. P.,

Zhao, L., Hudgens, C. W., Hutchinson, D. S., Manzo,

T., Petaccia De Macedo, M., Cotechini, T., Kumar, T.,

Chen, W. S., … Wargo, J. A. (2018). Gut microbiome

modulates response to anti-PD-1 immunotherapy in

melanoma patients. Science, 359(6371), 97–103.

https://doi.org/10.1126/science.aan4236

Mechanisms of Resistance to Cancer Immunotherapy

363

Gromeier, M., Brown, M. C., Zhang, G., Lin, X., Chen, Y.,

Wei, Z., Beaubier, N., Yan, H., He, Y., Desjardins, A.,

Herndon, J. E., Varn, F. S., Verhaak, R. G., Zhao, J.,

Bolognesi, D. P., Friedman, A. H., Friedman, H. S.,

McSherry, F., Muscat, A. M., … Ashley, D. M. (2021).

Very low mutation burden is a feature of inflamed

recurrent glioblastomas responsive to cancer

immunotherapy. Nature Communications, 12(1).

https://doi.org/10.1038/s41467-020-20469-6

Guo, Y., Pan, W., Liu, S., Shen, Z., Xu, Y., & Hu, L.

(2020). ERK/MAPK signalling pathway and

tumorigenesis. Experimental and Therapeutic

Medicine, 19(3), 1997.

https://doi.org/10.3892/etm.2020.8454

Haist, M., Stege, H., Grabbe, S., & Bros, M. (2021).

Review the functional crosstalk between myeloid-

derived suppressor cells and regulatory t cells within

the immunosuppressive tumor microenvironment. In

Cancers (Vol. 13, Issue 2, pp. 1–34). MDPI AG.

https://doi.org/10.3390/cancers13020210

Hansen, A. R., Massard, C., Ott, P. A., Haas, N. B., Lopez,

J. S., Ejadi, S., Wallmark, J. M., Keam, B., Delord, J.

P., Aggarwal, R., Gould, M., Yang, P., Keefe, S. M., &

Piha-Paul, S. A. (2018). Pembrolizumab for advanced

prostate adenocarcinoma: Findings of the KEYNOTE-

028 study. Annals of Oncology, 29(8), 1807–1813.

https://doi.org/10.1093/annonc/mdy232

Hasanali, Z. S., Saroya, B. S., Stuart, A., Shimko, S.,

Evans, J., Shah, M. V., Sharma, K., Leshchenko, V. V.,

Parekh, S., Loughran, T. P., & Epner, E. M. (2015).

Epigenetic therapy overcomes treatment resistance in T

cell prolymphocytic leukemia. Science Translational

Medicine, 7(293).

https://doi.org/10.1126/scitranslmed.aaa5079

Hegde, P. S., & Chen, D. S. (2020). Top 10 Challenges in

Cancer Immunotherapy. In Immunity (Vol. 52, Issue 1,

pp. 17–35). Cell Press.

https://doi.org/10.1016/j.immuni.2019.12.011

Hegde, P. S., Karanikas, V., & Evers, S. (2016). The where,

the when, and the how of immune monitoring for

cancer immunotherapies in the era of checkpoint

inhibition. Clinical Cancer Research, 22(8), 1865–

1874. https://doi.org/10.1158/1078-0432.CCR-15-

1507

Hellmann, M. D., Nathanson, T., Rizvi, H., Creelan, B. C.,

Sanchez-Vega, F., Ahuja, A., Ni, A., Novik, J. B.,

Mangarin, L. M. B., Abu-Akeel, M., Liu, C., Sauter, J.

L., Rekhtman, N., Chang, E., Callahan, M. K., Chaft, J.

E., Voss, M. H., Tenet, M., Li, X. M., … Wolchok, J.

D. (2018). Genomic Features of Response to

Combination Immunotherapy in Patients with

Advanced Non-Small-Cell Lung Cancer. Cancer Cell,

33(5), 843-852.e4.

https://doi.org/10.1016/j.ccell.2018.03.018

Hong, H., Wang, Q., Li, J., Liu, H., Meng, X., & Zhang, H.

(2019). Aging, cancer and immunity. Journal of

Cancer, 10(13), 3021–3027.

https://doi.org/10.7150/jca.30723

Hopkins-Donaldson, S., Ziegler, A., Kurtz, S., Bigosch, C.,

Kandioler, D., Ludwig, C., Zangemeister-Wittke, U., &

Stahel, R. (2003). Silencing of death receptor and

caspase-8 expression in small cell lung carcinoma cell

lines tumors by DNA methylation. Cell Death and

Differentiation, 10(3), 356–364.

https://doi.org/10.1038/sj.cdd.4401157

Hou, A., Hou, K., Huang, Q., Lei, Y., & Chen, W. (2020).

Targeting Myeloid-Derived Suppressor Cell, a

Promising Strategy to Overcome Resistance to Immune

Checkpoint Inhibitors. Frontiers in Immunology,

11(May), 1–19.

https://doi.org/10.3389/fimmu.2020.00783

Hoxhaj, G., & Manning, B. D. (2020). The PI3K–AKT

network at the interface of oncogenic signalling and

cancer metabolism. In Nature Reviews Cancer (Vol.

20, Issue 2, pp. 74–88). Nature Research.

https://doi.org/10.1038/s41568-019-0216-7

Huang, B., Pan, P. Y., Li, Q., Sato, A. I., Levy, D. E.,

Bromberg, J., Divino, C. M., & Chen, S. H. (2006). Gr-

1+CD115+ immature myeloid suppressor cells mediate

the development of tumor-induced T regulatory cells

and T-cell anergy in tumor-bearing host. Cancer

Research, 66(2), 1123–1131.

https://doi.org/10.1158/0008-5472.CAN-05-1299

Hugo, W., Zaretsky, J. M., Sun, L., Song, C., Homet, B.,

Hu-lieskovan, S., Berent-maoz, B., Pang, J.,

Chmielowski, B., Cherry, G., Seja, E., Lomeli, S.,

Kong, X., Kelley, M. C., Sosman, A., Johnson, D. B.,

Ribas, A., & Lo, R. S. (2017). Genomic and

transriptomic features of anti-PD1 response. Cell,

165(1), 35–44.

https://doi.org/10.1016/j.cell.2016.02.065.Genomic

Husain, Z., Huang, Y., Seth, P., & Sukhatme, V. P. (2013).

Tumor-Derived Lactate Modifies Antitumor Immune

Response: Effect on Myeloid-Derived Suppressor Cells

and NK Cells. The Journal of Immunology, 191(3),

1486–1495.

https://doi.org/10.4049/jimmunol.1202702

Insinga, A., Monestiroli, S., Ronzoni, S., Gelmetti, V.,

Marchesi, F., Viale, A., Altucci, L., Nervi, C., Minucci,

S., & Pelicci, P. G. (2005). Inhibitors of histone

deacetylases induce tumor-selective apoptosis through

activation of the death receptor pathway. Nature

Medicine, 11(1), 71–76.

https://doi.org/10.1038/nm1160

Italiani, P., & Boraschi, D. (2014). From monocytes to

M1/M2 macrophages: Phenotypical vs. functional

differentiation. Frontiers in Immunology, 5(OCT), 1–

22. https://doi.org/10.3389/fimmu.2014.00514

Jarnicki, A. G., Lysaght, J., Todryk, S., & Mills, K. H. G.

(2006). Suppression of Antitumor Immunity by IL-

10 and TGF-β-Producing T Cells Infiltrating the

Growing Tumor: Influence of Tumor Environment on

the Induction of CD4 + and CD8 + Regulatory T Cells

. The Journal of Immunology, 177(2), 896–904.

https://doi.org/10.4049/jimmunol.177.2.896

Jenkins, R. W., Barbie, D. A., & Flaherty, K. T. (2018).

Mechanisms of resistance to immune checkpoint

inhibitors. British Journal of Cancer, 118

(1), 9–16.

https://doi.org/10.1038/bjc.2017.434

ICBB 2022 - International Conference on Biotechnology and Biomedicine

364

Kalbasi, A., & Ribas, A. (2020). Tumour-intrinsic

resistance to immune checkpoint blockade. Nature

Reviews Immunology, 20(1), 25–39.

https://doi.org/10.1038/s41577-019-0218-4

Kloepper, J., Riedemann, L., Amoozgar, Z., Seano, G.,

Susek, K., Yu, V., Dalvie, N., Amelung, R. L., Datta,

M., Song, J. W., Askoxylakis, V., Taylor, J. W., Lu-

Emerson, C., Batista, A., Kirkpatrick, N. D., Jung, K.,

Snuderl, M., Muzikansky, A., Stubenrauch, K. G., …

Jain, R. K. (2016). Ang-2/VEGF bispecific antibody

reprograms macrophages and resident microglia to

anti-tumor phenotype and prolongs glioblastoma

survival. Proceedings of the National Academy of

Sciences of the United States of America, 113(16),

4476–4481. https://doi.org/10.1073/pnas.1525360113

Kumagai, S., Togashi, Y., Sakai, C., Kawazoe, A.,

Kawazu, M., Ueno, T., Sato, E., Kuwata, T., Kinoshita,

T., Yamamoto, M., Nomura, S., Tsukamoto, T., Mano,

H., Shitara, K., & Nishikawa, H. (2020). An Oncogenic

Alteration Creates a Microenvironment that Promotes

Tumor Progression by Conferring a Metabolic

Advantage to Regulatory T Cells. Immunity, 53(1),

187-203.e8.

https://doi.org/10.1016/j.immuni.2020.06.016

Kurachi, M. (2019). CD8 + T cell exhaustion. Seminars in

Immunopathology, 41(3), 327–337.

https://doi.org/10.1007/s00281-019-00744-5

Lastwika, K. J., Wilson, W., Li, Q. K., Norris, J., Xu, H.,

Ghazarian, S. R., Kitagawa, H., Kawabata, S., Taube,

J. M., Yao, S., Liu, L. N., Gills, J. J., & Dennis, P. A.

(2016). Control of PD-L1 expression by oncogenic

activation of the AKT-mTOR pathway in non-small

cell lung cancer. Cancer Research, 76(2), 227–238.

https://doi.org/10.1158/0008-5472.CAN-14-3362

Law, A. M. K., Valdes-Mora, F., & Gallego-Ortega, D.

(2020). Myeloid-Derived Suppressor Cells as a

Therapeutic Target for Cancer. Cells, 9(3).

https://doi.org/10.3390/cells9030561

Li, H., Han, Y., Guo, Q., Zhang, M., & Cao, X. (2009).

Cancer-Expanded Myeloid-Derived Suppressor Cells

Induce Anergy of NK Cells through Membrane-Bound

TGF-β1. The Journal of Immunology, 182(1), 240–249.

https://doi.org/10.4049/jimmunol.182.1.240

Liao, W., Overman, M. J., Boutin, A. T., Shang, X., Zhao,

D., Dey, P., Li, J., Wang, G., Lan, Z., Li, J., Tang, M.,

Jiang, S., Ma, X., Chen, P., Katkhuda, R., Korphaisarn,

K., Chakravarti, D., Chang, A., Spring, D. J., …

DePinho, R. A. (2019). KRAS-IRF2 Axis Drives

Immune Suppression and Immune Therapy Resistance

in Colorectal Cancer. Cancer Cell, 35(4), 559-572.e7.

https://doi.org/10.1016/j.ccell.2019.02.008

Limagne, E., Richard, C., Thibaudin, M., Fumet, J. D.,

Truntzer, C., Lagrange, A., Favier, L., Coudert, B., &

Ghiringhelli, F. (2019). Tim-3/galectin-9 pathway and

mMDSC control primary and secondary resistances to

PD-1 blockade in lung cancer patients.

OncoImmunology, 8(4), 1–13.

https://doi.org/10.1080/2162402X.2018.1564505

Lind, H., Gameiro, S. R., Jochems, C., Donahue, R. N.,

Strauss, J., Gulley, J. L., Palena, C., & Schlom, J.

(2020). Dual targeting of TGF-β and PD-L1 via a

bifunctional anti-PD-L1/TGF-βRII agent: Status of

preclinical and clinical advances. In Journal for

ImmunoTherapy of Cancer (Vol. 8, Issue 1). BMJ

Publishing Group. https://doi.org/10.1136/jitc-2019-

000433

Loi, S., Dushyanthen, S., Beavis, P. A., Salgado, R.,

Denkert, C., Savas, P., Combs, S., Rimm, D. L.,

Giltnane, J. M., Estrada, M. V., Sánchez, V., Sanders,

M. E., Cook, R. S., Pilkinton, M. A., Mallal, S. A.,

Wang, K., Miller, V. A., Stephens, P. J., Yelensky, R.,

… Balko, J. M. (2016). RAS/MAPK activation is

associated with reduced tumor-infiltrating lymphocytes

in triple-negative breast cancer: Therapeutic

cooperation between MEK and PD-1/PD-L1 immune

checkpoint inhibitors. Clinical Cancer Research,

22(6), 1499–1509. https://doi.org/10.1158/1078-

0432.CCR-15-1125

Long, L., Zhang, X., Chen, F., Pan, Q., Phiphatwatchara,

P., Zeng, Y., & Chen, H. (2018). The promising

immune checkpoint LAG-3: From tumor

microenvironment to cancer immunotherapy. Genes

and Cancer, 9(5–6), 176–189.

https://doi.org/10.18632/genesandcancer.180

Lukas, R. V., Rodon, J., Becker, K., Wong, E. T., Shih, K.,

Touat, M., Fassò, M., Osborne, S., Molinero, L.,

O’Hear, C., Grossman, W., & Baehring, J. (2018).

Clinical activity and safety of atezolizumab in patients

with recurrent glioblastoma. Journal of Neuro-

Oncology, 140(2), 317–328.

https://doi.org/10.1007/s11060-018-2955-9

Luke, J. J., Bao, R., Sweis, R. F., Spranger, S., & Gajewski,

T. F. (2019). WNT/b-catenin pathway activation

correlates with immune exclusion across human

cancers. Clinical Cancer Research, 25(10), 3074–

3083. https://doi.org/10.1158/1078-0432.CCR-18-

1942

Luo, N., Nixon, M. J., Gonzalez-Ericsson, P. I., Sanchez,

V., Opalenik, S. R., Li, H., Zahnow, C. A., Nickels, M.

L., Liu, F., Tantawy, M. N., Sanders, M. E., Manning,

H. C., & Balko, J. M. (2018). DNA methyltransferase

inhibition upregulates MHC-I to potentiate cytotoxic T

lymphocyte responses in breast cancer. Nature

Communications, 9(1), 1–11.

https://doi.org/10.1038/s41467-017-02630-w

Luu, M., Riester, Z., Baldrich, A., Reichardt, N., Yuille, S.,

Busetti, A., Klein, M., Wempe, A., Leister, H., Raifer,

H., Picard, F., Muhammad, K., Ohl, K., Romero, R.,

Fischer, F., Bauer, C. A., Huber, M., Gress, T. M.,

Lauth, M., … Steinhoff, U. (2021). Microbial short-

chain fatty acids modulate CD8+ T cell responses and

improve adoptive immunotherapy for cancer. Nature

Communications, 1–12.

https://doi.org/10.1038/s41467-021-24331-1

Madsen, R. R., Vanhaesebroeck, B., & Semple, R. K.

(2018). Cancer-Associated PIK3CA Mutations in

Overgrowth Disorders. Trends in Molecular Medicine,

24(10), 856–870.

https://doi.org/10.1016/j.molmed.2018.08.003

Mechanisms of Resistance to Cancer Immunotherapy

365

Maio, M., Covre, A., Fratta, E., Di Giacomo, A. M.,

Taverna, P., Natali, P. G., Coral, S., & Sigalotti, L.

(2015). Molecular pathways: At the crossroads of

cancer epigenetics and immunotherapy. Clinical

Cancer Research, 21(18), 4040–4047.

https://doi.org/10.1158/1078-0432.CCR-14-2914

Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A.,

Yuen, K., Wang, Y., Kadel, E. E., Koeppen, H.,

Astarita, J. L., Cubas, R., Jhunjhunwala, S.,

Banchereau, R., Yang, Y., Guan, Y., Chalouni, C., Ziai,

J., Şenbabaoǧlu, Y., Santoro, S., Sheinson, D., …

Powles, T. (2018). TGFβ attenuates tumour response to

PD-L1 blockade by contributing to exclusion of T cells.

Nature, 554(7693), 544–548.

https://doi.org/10.1038/nature25501

Matson, V., Fessler, J., Bao, R., Chongsuwat, T., Zha, Y.,

Alegre, M. L., Luke, J. J., & Gajewski, T. F. (2018).

The commensal microbiome is associated with anti-

PD-1 efficacy in metastatic melanoma patients.

Science, 359(6371), 104–108.

https://doi.org/10.1126/science.aao3290

Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D.

M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z.,

Lacey, S. F., Mahnke, Y. D., Melenhorst, J. J.,

Rheingold, S. R., Shen, A., Teachey, D. T., Levine, B.

L., June, C. H., Porter, D. L., & Grupp, S. A. (2014).

Chimeric Antigen Receptor T Cells for Sustained

Remissions in Leukemia. New England Journal of

Medicine, 371(16), 1507–1517.

https://doi.org/10.1056/nejmoa1407222

Mcgranahan, N., Furness, A. J. S., Rosenthal, R., Lyngaa,

R., Saini, S. K., Jamal-hanjani, M., Gareth, A., Birkbak,

N. J., Hiley, C. T., Watkins, T. B. K., Shafi, S.,

Murugaesu, N., Mitter, R., Akarca, A. U., Linares, J.,

Henry, J. Y., Allen, E. M. Van, Miao, D., & Schilling,

B. (2016). Clonal neoantigens elicit T cell

immunoreactivity and sensitivity to immune

checkpoint blockade. Science, 351(6280), 1463–1469.

https://doi.org/10.1126/science.aaf1490.Clonal

Mcgranahan, N., Rosenthal, R., Hiley, C. T., Herrero, J., &

Swanton, C. (2017). Allele-Specific HLA Loss and

Immune Escape in Lung Cancer Evolution. Cell,

171(6), 1259–1271.

https://doi.org/https://doi.org/10.1016/j.cell.2017.10.0

Meissner, M., Reichert, T. E., Kunkel, M., Gooding, W.,

Whiteside, T. L., Ferrone, S., & Seliger, B. (2005).

Defects in the human leukocyte antigen class I antigen-

processing machinery in head and neck squamous cell

carcinoma: Association with clinical outcome. Clinical

Cancer Research, 11(7), 2552–2560.

https://doi.org/10.1158/1078-0432.CCR-04-2146

Mo, X., Zhang, H., Preston, S., Martin, K., Zhou, B.,

Vadalia, N., Gamero, A. M., Soboloff, J., Tempera, I.,

& Zaidi, M. R. (2018). Interferon-γ Signaling in

Melanocytes and Melanoma Cells Regulates

Expression of CTLA-4. Cancer Research, 78(2), 436–

450. https://doi.org/10.1158/0008-5472.CAN-17-1615

Mosser, D. M., & Edwards, J. P. (2008). Exploring the full

spectrum of macrophage activation. Nature Reviews

Immunology, 8(12), 958–969.

https://doi.org/10.1038/nri2448

Müller, B., Fischer, B., & Kreutz, W. (2000). An acidic

microenvironment impairs the generation of non-major

histocompatibility complex-restricted killer cells.

Immunology, 99(3), 375–384.

https://doi.org/10.1046/j.1365-2567.2000.00975.x

Munder, M., Schneider, H., Luckner, C., Giese, T.,

Langhans, C. D., Fuentes, J. M., Kropf, P., Mueller, I.,

Kolb, A., Modolell, M., & Ho, A. D. (2006).

Suppression of T-cell functions by human granulocyte

arginase. Blood, 108(5), 1627–1634.

https://doi.org/10.1182/blood-2006-11-010389

Nagarsheth, N., Peng, D., Kryczek, I., Wu, K., Li, W.,

Zhao, E., Zhao, L., Wei, S., Frankel, T., Vatan, L.,

Szeliga, W., Dou, Y., Owens, S., Marquez, V., Tao, K.,

Huang, E., Wang, G., & Zou, W. (2016). PRC2

epigenetically silences Th1-type chemokines to

suppress effector T-cell trafficking in colon cancer.

Cancer Research, 76(2), 275–282.

https://doi.org/10.1158/0008-5472.CAN-15-1938

Najjar, Y. G., Rayman, P., Jia, X., Pavicic, P. G., Rini, B.

I., Tannenbaum, C., Ko, J., Haywood, S., Cohen, P.,

Hamilton, T., Diaz-Montero, C. M., & Finke, J. (2017).

Myeloid-derived suppressor cell subset accumulation

in renal cell carcinoma parenchyma is associated with

intratumoral expression of IL1b, IL8, CXCL5, and

Mip-1α. Clinical Cancer Research, 23(9), 2346–2355.

https://doi.org/10.1158/1078-0432.CCR-15-1823

Ni, L., & Lu, J. (2018). Interferon gamma in cancer

immunotherapy. In Cancer Medicine (Vol. 7, Issue 9,

pp. 4509–4516). Blackwell Publishing Ltd.

https://doi.org/10.1002/cam4.1700

Nowicki, T. S., Hu-Lieskovan, S., & Ribas, A. (2018).

Mechanisms of Resistance to PD-1 and PD-L1

Blockade. In Cancer Journal (United States) (Vol. 24,

Issue 1, pp. 47–53). Lippincott Williams and Wilkins.

https://doi.org/10.1097/PPO.0000000000000303

Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne,

S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen,

D. R., Kurachi, M., Barnitz, R. A., Bartman, C.,

Bengsch, B., Huang, A. C., Schenkel, J. M., Vahedi,

G., Haining, W. N., Berger, S. L., & Wherry, E. J.

(2016). Epigenetic stability of exhausted T cells limits

durability of reinvigoration by PD-1 blockade. Science,

354(6316), 1160–1165.

https://doi.org/10.1126/science.aaf2807

Peng, D., Kryczek, I., Nagarsheth, N., Zhao, L., Wei, S.,

Wang, W., Sun, Y., Zhao, E., Vatan, L., Szeliga, W.,

Kotarski, J., Tarkowski, R., Dou, Y., Cho, K., Hensley-

Alford, S., Munkarah, A., Liu, R., & Zou, W. (2015).

Epigenetic silencing of TH1-type chemokines shapes

tumour immunity and immunotherapy. Nature,

527(7577), 249–253.

https://doi.org/10.1038/nature15520

Peng, W., Chen, J. Q., Liu, C., Malu, S., Creasy, C.,

Tetzlaff, M. T., Xu, C., McKenzie, J. A., Zhang, C.,

Liang, X., Williams, L. J., Deng, W., Chen, G.,

Mbofung, R., Lazar, A. J., Torres-Cabala, C. A.,

Cooper, Z. A., Chen, P.-L., Tieu, T. N., … Hwu, P.

ICBB 2022 - International Conference on Biotechnology and Biomedicine

366

(2016). Loss of PTEN Promotes Resistance to T Cell–

Mediated Immunotherapy. Cancer Discovery, 6(2),

202–216. https://doi.org/10.1158/2159-8290.CD-15-

0283

Perumal, D., Imai, N., Lagana, A., Finnigan, J., Melnekoff,

D., Leshchenko, V. V., Solovyov, A., Madduri, D.,

Chari, A., Cho, H. J., Dudley, J. T., Brody, J. D.,

Jagannath, S., Greenbaum, B., Gnjatic, S., Bhardwaj,

N., & Parekh, S. (2020). Mutation-derived Neoantigen-

specific T-cell Responses in Multiple Myeloma.

Clinical Cancer Research, 26(2), 450–464.

https://doi.org/10.1158/1078-0432.CCR-19-2309

Porta, C., Paglino, C., & Mosca, A. (2014). Targeting

PI3K/Akt/mTOR signaling in cancer. In Frontiers in

Oncology: Vol. 4 APR. Frontiers Research Foundation.

https://doi.org/10.3389/fonc.2014.00064

Rech, A. J., Mick, R., Martin, S., Recio, A., Aqui, N. A.,

Powell, D. J., Colligon, T. A., Trosko, J. A., Leinbach,

L. I., Pletcher, C. H., Tweed, C. K., DeMichele, A.,

Fox, K. R., Domchek, S. M., Riley, J. L., &

Vonderheide, R. H. (2012). CD25 blockade depletes

and selectively reprograms regulatory T cells in concert

with immunotherapy in cancer patients. Science

Translational Medicine, 4(134), 134ra62.

https://doi.org/10.1126/scitranslmed.3003330

Reeves, E., & James, E. (2017). Antigen processing and

immune regulation in the response to tumours.

Immunology, 150(1), 16–24.

https://doi.org/10.1111/imm.12675

Reinfeld, B. I., Madden, M. Z., Wolf, M. M., Chytil, A.,

Bader, J. E., Patterson, A. R., Sugiura, A., Cohen, A.

S., Ali, A., Do, B. T., Muir, A., Lewis, C. A., Hongo,

R. A., Young, K. L., Brown, R. E., Todd, V. M.,

Huffstater, T., Abraham, A., O’Neil, R. T., …

Rathmell, W. K. (2021). Cell-programmed nutrient

partitioning in the tumour microenvironment. Nature,

593(7858), 282–288. https://doi.org/10.1038/s41586-

021-03442-1

Reisländer, T., Lombardi, E. P., Groelly, F. J., Miar, A.,

Porru, M., Di Vito, S., Wright, B., Lockstone, H.,

Biroccio, A., Harris, A., Londoño-Vallejo, A., &

Tarsounas, M. (2019). BRCA2 abrogation triggers

innate immune responses potentiated by treatment with

PARP inhibitors. Nature Communications, 10(1),

3143. https://doi.org/10.1038/s41467-019-11048-5

Ribas, A., & Wolchok, J. D. (2018). Cancer

immunotherapy using checkpoint blockade. In Science

(Vol. 359, Issue 6382, pp. 1350–1355). American

Association for the Advancement of Science.

https://doi.org/10.1126/science.aar4060

Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P.,

Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P.,

Ho, T. S., Miller, M. L., Rekhtman, N., Moreira, A. L.,

Ibrahim, F., Bruggeman, C., Gasmi, B., Zappasodi, R.,

Maeda, Y., Sander, C., … Chan, T. A. (2015).

Mutational landscape determines sensitivity to PD-1

blockade in non-small cell lung cancer. Science,

348(6230), 124–128.

https://doi.org/10.1126/science.aaa1348

Rodriguez, P. C., Quiceno, D. G., & Ochoa, A. C. (2007).

L-arginine availability regulates T-lymphocyte cell-

cycle progression. Blood, 109(4), 1568–1573.

https://doi.org/10.1182/blood-2006-06-031856

Rosenthal, R., Cadieux, E. L., Salgado, R., Bakir, M. Al,

Moore, D. A., Hiley, C. T., Lund, T., Tanić, M.,

Reading, J. L., Joshi, K., Henry, J. Y., Ghorani, E.,

Wilson, G. A., Nicolai, J., Hellmann, M. D., Feber, A.,

Chain, B., & Herrero, J. (2020). Neoantigen directed

immune escape in lung cancer evolution. Nature,

567(7749), 479–485. https://doi.org/10.1038/s41586-

019-1032-7.Neoantigen

Rotte, A. (2019). Combination of CTLA-4 and PD-1

blockers for treatment of cancer. In Journal of

Experimental and Clinical Cancer Research (Vol. 38,

Issue 1). BioMed Central Ltd.

https://doi.org/10.1186/s13046-019-1259-z

Ryzhov, S., Novitskiy, S. V., Goldstein, A. E., Biktasova,

A., Blackburn, M. R., Biaggioni, I., Dikov, M. M., &

Feoktistov, I. (2011). Adenosinergic Regulation of

the Expansion and Immunosuppressive Activity of

CD11b + Gr1 + Cells . The Journal of Immunology,

187(11), 6120–6129.

https://doi.org/10.4049/jimmunol.1101225

Sahin, U., Derhovanessian, E., Miller, M., Kloke, B.-P.,

Simon, P., Löwer, M., Bukur, V., Tadmor, A. D.,

Luxemburger, U., Schrörs, B., Omokoko, T., Vormehr,

M., Albrecht, C., Paruzynski, A., Kuhn, A. N., Buck,

J., Heesch, S., Schreeb, K. H., Müller, F., … Türeci, Ö.

(2017). Personalized RNA mutanome vaccines

mobilize poly-specific therapeutic immunity against

cancer. Nature, 547(7662), 222–226.

https://doi.org/10.1038/nature23003

Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R.,

Kuchroo, V. K., & Anderson, A. C. (2010). Targeting

Tim-3 and PD-1 pathways to reverse T cell exhaustion

and restore anti-tumor immunity. Journal of

Experimental Medicine, 207(10), 2187–2194.

https://doi.org/10.1084/jem.20100643

Sasidharan Nair, V., El Salhat, H., Taha, R. Z., John, A.,

Ali, B. R., & Elkord, E. (2018). DNA methylation and

repressive H3K9 and H3K27 trimethylation in the

promoter regions of PD-1, CTLA-4, TIM-3, LAG-3,

TIGIT, and PD-L1 genes in human primary breast

cancer. Clinical Epigenetics, 10(1), 1–12.

https://doi.org/10.1186/s13148-018-0512-1

Schumacher, T. N., & Schreiber, R. D. (2015). Neoantigens

in cancer immunotherapy. Science, 348(6230), 69–74.

https://doi.org/10.1126/science.aaa4971

Seidel, J. A., Otsuka, A., & Kabashima, K. (2018). Anti-

PD-1 and anti-CTLA-4 therapies in cancer:

Mechanisms of action, efficacy, and limitations.

Frontiers in Oncology, 8(MAR), 1–14.

https://doi.org/10.3389/fonc.2018.00086

Sek, K., Mølck, C., Stewart, G. D., Kats, L., Darcy, P. K.,

& Beavis, P. A. (2018). Targeting adenosine receptor

signaling in cancer immunotherapy. International

Journal of Molecular Sciences, 19(12).

https://doi.org/10.3390/ijms19123837

Mechanisms of Resistance to Cancer Immunotherapy

367

SELIGER, B., DUNN, T., SCHWENZER, A., CASPER,

J., HUBER, C., & SCHMOLL, H. J. (1997). Analysis

of the MHC Class I Antigen Presentation Machinery in

Human Embryonal Carcinomas: Evidence for

Deficiencies in TAP, LMP and MHC Class I

Expression and their Upregulation by IFN‐γ.

Scandinavian Journal of Immunology, 46(6), 625–632.

https://doi.org/10.1046/j.1365-3083.1997.d01-176.x

Setiadi, A. F., David, M. D., Seipp, R. P., Hartikainen, J.

A., Gopaul, R., & Jefferies, W. A. (2007). Epigenetic

Control of the Immune Escape Mechanisms in

Malignant Carcinomas. Molecular and Cellular

Biology, 27(22), 7886–7894.

https://doi.org/10.1128/mcb.01547-07

Sharma, P., Pachynski, R. K., Narayan, V., Fléchon, A.,

Gravis, G., Galsky, M. D., Mahammedi, H., Patnaik,

A., Subudhi, S. K., Ciprotti, M., Simsek, B., Saci, A.,

Hu, Y., Han, G. C., & Fizazi, K. (2020). Nivolumab

Plus Ipilimumab for Metastatic Castration-Resistant

Prostate Cancer: Preliminary Analysis of Patients in the

CheckMate 650 Trial. Cancer Cell, 38(4), 489-499.e3.

https://doi.org/10.1016/j.ccell.2020.08.007

Shin, D. S., Zaretsky, J. M., Escuin-Ordinas, H., Garcia-

Diaz, A., Hu-Lieskovan, S., Kalbasi, A., Grasso, C. S.,

Hugo, W., Sandoval, S., Torrejon, D. Y., Palaskas, N.,

Abril-Rodriguez, G., Parisi, G., Azhdam, A.,

Chmielowski, B., Cherry, G., Seja, E., Berent-Maoz,

B., Shintaku, I. P., … Ribas, A. (2017). Primary

resistance to PD-1 blockade mediated by JAK1/2

mutations. Cancer Discovery, 7(2), 188–201.

https://doi.org/10.1158/2159-8290.CD-16-1223

Sivan, A., Corrales, L., Hubert, N., Williams, J. B., Aquino-

Michaels, K., Earley, Z. M., Benyamin, F. W., Lei, Y.

M., Jabri, B., Alegre, M. L., Chang, E. B., & Gajewski,

T. F. (2015). Commensal Bifidobacterium promotes

antitumor immunity and facilitates anti-PD-L1

efficacy. Science, 350(6264), 1084–1089.

https://doi.org/10.1126/science.aac4255

Snahnicanova, Z., Kasubova, I., Kalman, M., Grendar, M.,

Mikolajcik, P., Gabonova, E., Laca, L., Caprnda, M.,

Rodrigo, L., Ciccocioppo, R., Kruzliak, P., Plank, L.,

& Lasabova, Z. (2020). Genetic and epigenetic analysis

of the beta-2-microglobulin gene in microsatellite

instable colorectal cancer. Clinical and Experimental

Medicine, 20(1), 87–95.

https://doi.org/10.1007/s10238-019-00601-7

Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky,

J. M., Desrichard, A., Walsh, L. A., Postow, M. A.,

Wong, P., Ho, T. S., Hollmann, T. J., Bruggeman, C.,

Kannan, K., Li, Y., Elipenahli, C., Liu, C., Harbison,

C. T., Wang, L., Ribas, A., … Chan, T. A. (2014).

Genetic Basis for Clinical Response to CTLA-4

Blockade in Melanoma. New England Journal of

Medicine, 371(23), 2189–2199.

https://doi.org/10.1056/nejmoa1406498

Spranger, S., Bao, R., & Gajewski, T. F. (2015).

Melanoma-intrinsic β-catenin signalling prevents anti-

tumour immunity. Nature

, 523(7559), 231–235.

https://doi.org/10.1038/nature14404

Spranger, S., Koblish, H. K., Horton, B., Scherle, P. A.,

Newton, R., & Gajewski, T. F. (2014). Mechanism of

tumor rejection with doublets of CTLA-4, PD-1/PD-

L1, or IDO blockade involves restored IL-2 production

and proliferation of CD8+ T cells directly within the

tumor microenvironment. Journal for ImmunoTherapy

of Cancer, 2(1), 1–14. https://doi.org/10.1186/2051-

1426-2-3

Srivastava, M. K., Sinha, P., Clements, V. K., Rodriguez,

P., & Ostrand-Rosenberg, S. (2010). Myeloid-derived

suppressor cells inhibit T-cell activation by depleting

cystine and cysteine. Cancer Research, 70(1), 68–77.

https://doi.org/10.1158/0008-5472.CAN-09-2587

Stary, G., Olive, A., Radovic-Moreno, A. F., Gondek, D.,

Alvarez, D., Basto, P. A., Perro, M., Vrbanac, V. D.,

Tager, A. M., Shi, J., Yethon, J. A., Farokhzad, O. C.,

Langer, R., Starnbach, M. N., & von Andrian, U. H.

(2015). VACCINES. A mucosal vaccine against

Chlamydia trachomatis generates two waves of

protective memory T cells. Science (New York, N.Y.),

348(6241), aaa8205.

https://doi.org/10.1126/science.aaa8205

Strickler, J. H., Hanks, B. A., & Khasraw, M. (2021).

Tumor mutational burden as a predictor of

immunotherapy response: Is more always better? In

Clinical Cancer Research (Vol. 27, Issue 5, pp. 1236–

1241). American Association for Cancer Research Inc.

https://doi.org/10.1158/1078-0432.CCR-20-3054

Sumimoto, H., Takano, A., Teramoto, K., & Daigo, Y.

(2016). RAS-mitogen-activated protein kinase signal is

required for enhanced PD-L1 expression in human lung

cancers. PLoS ONE, 11(11), 1–18.

https://doi.org/10.1371/journal.pone.0166626

Takeuchi, Y., & Nishikawa, H. (2016). Roles of regulatory

T cells in cancer immunity. International Immunology,

28(8), 401–409.

https://doi.org/10.1093/intimm/dxw025

Turnis, M. E., Sawant, D. V., Szymczak-Workman, A. L.,

Andrews, L. P., Delgoffe, G. M., Yano, H., Beres, A.

J., Vogel, P., Workman, C. J., & Vignali, D. A. A.

(2016). Interleukin-35 Limits Anti-Tumor Immunity.

Immunity, 44(2), 316–329.

https://doi.org/10.1016/j.immuni.2016.01.013

Veldman, J., Visser, L., Berg, A. van den, & Diepstra, A.

(2020). Primary and acquired resistance mechanisms to

immune checkpoint inhibition in Hodgkin lymphoma.

In Cancer Treatment Reviews (Vol. 82). W.B. Saunders

Ltd. https://doi.org/10.1016/j.ctrv.2019.101931

Vétizou, M., Pitt, J. M., Daillère, R., Lepage, P.,

Waldschmitt, N., Flament, C., Rusakiewicz, S., Routy,

B., Roberti, M. P., Duong, C. P. M., Poirier-Colame,

V., Roux, A., Becharef, S., Formenti, S., Golden, E.,

Cording, S., Eberl, G., Schlitzer, A., Ginhoux, F., …

Zitvogel, L. (2015). Anticancer immunotherapy by

CTLA-4 blockade relies on the gut microbiota. Science,

350(6264), 1079–1084.

https://doi.org/10.1126/science.aad1329

Voron, T., Marcheteau, E., Pernot, S., Colussi, O., Tartour,

E., Taieb, J., & Terme, M. (2014). Control of the

immune response by pro-angiogenic factors. Frontiers

ICBB 2022 - International Conference on Biotechnology and Biomedicine

368

in Oncology, 4 APR(April), 1–9.

https://doi.org/10.3389/fonc.2014.00070

Wallis, C. J. D., Butaney, M., Satkunasivam, R., Freedland,

S. J., Patel, S. P., Hamid, O., Pal, S. K., & Klaassen, Z.

(2019). Association of Patient Sex with Efficacy of

Immune Checkpoint Inhibitors and Overall Survival in

Advanced Cancers: A Systematic Review and Meta-

analysis. JAMA Oncology, 5(4), 529–536.

https://doi.org/10.1001/jamaoncol.2018.5904

Wang, J., Li, D., Cang, H., & Guo, B. (2019). Crosstalk

between cancer and immune cells: Role of tumor-

associated macrophages in the tumor

microenvironment. Cancer Medicine, 8(10), 4709–

4721. https://doi.org/10.1002/cam4.2327

Warburg, O. (1956). On the origin of cancer cells. Science,

123(3191), 309–314.

https://doi.org/10.1126/science.123.3191.309

Warburg, O., Wind, F., & Negelein, E. (1927). THE

METABOLISM OF TUMORS IN THE BODY.

Journal of General Physiology, 8(6), 519–530.

https://doi.org/10.1085/jgp.8.6.519

Weber, J. S., Kudchadkar, R. R., Yu, B., Gallenstein, D.,

Horak, C. E., Inzunza, H. D., Zhao, X., Martinez, A. J.,

Wang, W., Gibney, G., Kroeger, J., Eysmans, C.,

Sarnaik, A. A., & Chen, Y. A. (2013). Safety, efficacy,

and biomarkers of nivolumab with vaccine in

ipilimumab-refractory or -naive melanoma. Journal of

Clinical Oncology, 31(34), 4311–4318.

https://doi.org/10.1200/JCO.2013.51.4802

Wylie, B., Chee, J., Forbes, C. A., Booth, M., Stone, S. R.,

Buzzai, A., Abad, A., Foley, B., Cruickshank, M. N., &

Waithman, J. (2019). Acquired resistance during

adoptive cell therapy by transcriptional silencing of

immunogenic antigens. OncoImmunology, 8(8), 1–11.

https://doi.org/10.1080/2162402X.2019.1609874

Xiong, D., Wang, Y., Singavi, A. K., Mackinnon, A. C.,

George, B., & You, M. (2018). Immunogenomic

Landscape Contributes to Hyperprogressive Disease

after Anti-PD-1 Immunotherapy for Cancer. IScience,

9, 258–277. https://doi.org/10.1016/j.isci.2018.10.021

Yaguchi, T., Goto, Y., Kido, K., Mochimaru, H., Sakurai,

T., Tsukamoto, N., Kudo-Saito, C., Fujita, T.,

Sumimoto, H., & Kawakami, Y. (2012). Immune

Suppression and Resistance Mediated by Constitutive

Activation of Wnt/β-Catenin Signaling in Human

Melanoma Cells. The Journal of Immunology, 189(5),

2110–2117.

https://doi.org/10.4049/jimmunol.1102282

Yan, C., Yang, J., Saleh, N., Chen, S.-C., Ayers, G. D.,

Abramson, V. G., Mayer, I. A., & Richmond, A.

(2021). Inhibition of the PI3K/mTOR Pathway in

Breast Cancer to Enhance Response to Immune

Checkpoint Inhibitors in Breast Cancer. International

Journal of Molecular Sciences, 22(10), 5207.

https://doi.org/10.3390/ijms22105207

Yang, F., Markovic, S. N., Molina, J. R., Halfdanarson, T.

R., Pagliaro, L. C., Chintakuntlawar, A. V., Li, R., Wei,

J., Wang, L., Liu, B., Nowakowski, G. S., Wang, M. L.,

& Wang, Y. (2020). Association of Sex, Age, and

Eastern Cooperative Oncology Group Performance

Status with Survival Benefit of Cancer Immunotherapy

in Randomized Clinical Trials: A Systematic Review

and Meta-analysis. JAMA Network Open, 3(8), 1–11.

https://doi.org/10.1001/jamanetworkopen.2020.12534

Yang, H., Zhang, Q., Xu, M., Wang, L., Chen, X., Feng,

Y., Li, Y., Zhang, X., Cui, W., & Jia, X. (2020). CCL2-

CCR2 axis recruits tumor associated macrophages to

induce immune evasion through PD-1 signaling in

esophageal carcinogenesis. Molecular Cancer, 19(1),

41. https://doi.org/10.1186/s12943-020-01165-x

Yang, Z., Zhang, B., Li, D., Lv, M., Huang, C., Shen, G.

X., & Huang, B. (2010). Mast cells mobilize myeloid-

derived suppressor cells and Treg cells in tumor

microenvironment via IL-17 pathway in murine

hepatocarcinoma model. PLoS ONE, 5(1), 1–9.

https://doi.org/10.1371/journal.pone.0008922

Yu, J., Du, W., Yan, F., Wang, Y., Li, H., Cao, S., Yu, W.,

Shen, C., Liu, J., & Ren, X. (2013). Myeloid-Derived

Suppressor Cells Suppress Antitumor Immune

Responses through IDO Expression and Correlate with

Lymph Node Metastasis in Patients with Breast

Cancer. The Journal of Immunology, 190(7), 3783–

3797. https://doi.org/10.4049/jimmunol.1201449

Zakharia, Y., McWilliams, R. R., Rixe, O., Drabick, J.,

Shaheen, M. F., Grossmann, K. F., Kolhe, R.,

Pacholczyk, R., Sadek, R., Tennant, L. L., Smith, C.

M., Kennedy, E. P., Link, C. J., Vahanian, N. N., Yu,

J., Shen, S. S., Brincks, E. L., Rossi, G. R., Munn, D.,

& Milhem, M. (2021). Phase II trial of the IDO

pathway inhibitor indoximod plus pembrolizumab for

the treatment of patients with advanced melanoma.

Journal for ImmunoTherapy of Cancer, 9(6).

https://doi.org/10.1136/jitc-2020-002057

Zaretsky, J. M., Garcia-Diaz, A., Shin, D. S., Escuin-

Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D.

Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L.,

Saco, J., Homet Moreno, B., Mezzadra, R.,

Chmielowski, B., Ruchalski, K., Shintaku, I. P.,

Sanchez, P. J., Puig-Saus, C., Cherry, G., … Ribas, A.

(2016). Mutations Associated with Acquired

Resistance to PD-1 Blockade in Melanoma. New

England Journal of Medicine, 375(9), 819–829.

https://doi.org/10.1056/nejmoa1604958

Zhang, Y., & Wang, X. (2020). Targeting the Wnt/β-

catenin signaling pathway in cancer. In Journal of

Hematology and Oncology (Vol. 13, Issue 1). BioMed

Central Ltd. https://doi.org/10.1186/s13045-020-

00990-3

Mechanisms of Resistance to Cancer Immunotherapy

369