Cancer Letters 473 (2020) 148–155

Contents lists available at ScienceDirect

Cancer Letters
journal homepage: www.elsevier.com/locate/canlet

Mini-review

ARID1A deficiency and immune checkpoint blockade therapy: From T

mechanisms to clinical application
Guangyuan Hua,1, Wei Tub,1, Liu Yangc, Guang Pengd, Lin Yanga,∗
a
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
b
Department of Rheumatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
c
Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
d
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

A R T I C LE I N FO A B S T R A C T

Keywords: The AT-rich interaction domain 1A (ARID1A, also known as BAF250a) is a chromatin remodeling gene, which
Chromatin remodeling gene frequently mutates across a broad spectrum of cancers with loss expression of the ARID1A protein. Recently, the
Immunotherapy association between ARID1A deficiency and immune checkpoint blockade (ICB) therapy has been reported.
Predictive biomarker ARID1A deficiency contributes to the high microsatellite instability phenotype, increases tumor mutation
Combined therapy
burden, elevates expression of programmed cell death ligand 1 (PD-L1), and modulates the immune micro-
environment, supporting the view that ARID1A loss might serve as a predictive biomarker for ICB. Furthermore,
the therapeutic targeting strategies, which show “synthetic lethality” with ARID1A deficiency, exhibit potential
synergy with ICB. We collectively reviewed the mechanisms underlying the correlation between ARID1A defi-
ciency and ICB, the predictive function of ARID1A deficiency for ICB, and potential combined strategies of
targeting agents, vulnerable for ARID1A deficiency, with ICB in cancer treatment.

1. Introduction the consideration of this gene as a tumor suppressor, which was con-
firmed in endometrial cancer, pancreatic cancer, and colon cancer
SWItch/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling [2,7–9]. Recently, ARID1A was found to have context-dependent on-
complex mobilizes nucleosomes to regulate the accessibility of DNA cogenic and tumor suppressor functions in liver cancer [10]. Moreover,
using energy provided by ATP hydrolysis, which modulates diverse inactivation of ARID1A enhances TERT transcription and maintains
cellular processes, including transcription, replication, and DNA da- telomere length in cancer cells, which is in accordance with its tumor
mage repair [1]. The AT-rich interaction domain 1A (ARID1A, also suppressor function [11]. Meanwhile, ARID1A has been indicated to be
known as BAF250a), encoding a subunit of SWI/SNF complex, is among involved in DNA damage repair, through interaction with the crucial
the most commonly mutated genes across a wide array of cancers, upstream checkpoint kinase, ataxia telangiectasia and rad3-related
especially in ovarian clear cell carcinoma (up to 60%), uterine corpus (ATR) kinase [12]. Additionally, ARID1A controls global transcription
endometrial carcinoma, stomach adenocarcinoma, hepatocellular car- by pausing RNA polymerase Ⅱ [13]. Consistently, the ARID1A defi-
cinoma, and urothelial bladder carcinoma [1–3]. The majority of ciency is characterized by mutability and a genomic instability phe-
ARID1A mutations are inactivating nonsense or frame-shift mutations, notype [14].
and result in loss of expression of the ARID1A protein [4–6]. Currently, immune checkpoint blockade (ICB) therapy has led to a
As a chromatin remodeler, ARID1A is implicated in various cellular paradigm shift in cancer treatment due to durable and robust responses.
functions. Initially, the frequent inactivation of ARID1A in cancer led to For diverse cancers, such as melanoma, renal cancer and lung cancer,

Abbreviations: SWI/SNF, SWItch/Sucrose Non-Fermenting; ARID1A, the AT-rich interaction domain 1A; ICB, immune checkpoint blockade; MSI, microsatellite
instability; TMB, tumor mutation burden; PD-L1, programmed cell death ligand 1; TME, tumor microenvironment; PARP, poly (ADP-ribose) polymerase; ATR, ataxia
telangiectasia and rad3-related; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; EZH2, enhancer of zeste homolog 2; HDAC6, histone deacetylase 6; ICIs,
immune checkpoint inhibitors
∗
Corresponding author.
E-mail addresses: [email protected] (G. Hu), [email protected] (W. Tu), [email protected] (L. Yang), [email protected] (G. Peng),
[email protected] (L. Yang).
1
Guangyuan Hu and Wei Tu were the co-first authors.

https://doi.org/10.1016/j.canlet.2020.01.001
Received 6 November 2019; Received in revised form 15 December 2019; Accepted 1 January 2020
0304-3835/ © 2020 Elsevier B.V. All rights reserved.
G. Hu, et al. Cancer Letters 473 (2020) 148–155

the main ICB therapies, including monoclonal antibodies targeting T more recent study found that ARID1A recruited MMR protein MSH2 to
lymphocyte-associated protein 4 (CTLA-4) and programmed cell death chromatin and facilitated MMR. Consequently, ARID1A inactivation
protein 1 (PD-1) or its primary ligand programmed cell death ligand 1 impaired MMR and led to MSI-H genomic signature, which increased
(PD-L1), stimulate antitumor immune responses and show significant mutagenesis. Moreover, the authors showed that mice xenograft
clinical success [15–17]. For example, in previously treated advanced models, with ARID1A-deficient but not ARID1A-wild-type ovarian
non-small-cell lung cancer (NSCLC), nivolumab, a PD-1 antibody, sur- cancers, were especially sensitive to anti-PD-L1 antibody [14].
prisingly elevated the 4-year survival rate from 5% by traditional
chemotherapy to 14% from pooled analysis of CheckMate 017 and 2.2. TMB
CheckMate 057, which were two phase 3 clinical trials investigating the
efficacy of nivolumab in comparison to that of chemotherapy in ad- TMB is a predictive biomarker for ICB, as demonstrated by large
vanced squamous and non-squamous NSCLC [18]. clinical trials, although controversy still exists [29,30]. TMB has been
However, the objective response rate (ORR) of ICB is still as low as considered as a marker of genomic instability in cancer, which corre-
approximately 20%, indicating that only a minority of patients with lates closely with the capacity of DNA damage repair (DDR) [31]. As
advanced cancers benefit from ICB [17,19]. Therefore, predicting the previously acknowledged, dysfunction of DDR leads to accumulated
response to ICB, and overcoming the narrow therapeutic window, re- DNA damage, and a predisposition for cancer. The crucial DDR up-
main the greatest challenges during clinical application. To date, no stream checkpoint kinase ATR has been validated to interact with
well accepted biomarkers for ICB therapy have been established. Re- ARID1A, which is necessary for the efficient repair of DNA double-
sults regarding the most commonly used biomarkers, like the expression strand breaks (DSBs) and sustaining DNA damage signaling [12].
of PD-L1 and tumor mutation burden (TMB), contradict each other. Consistently, ARID1A deficiency results in predominant C > T muta-
Furthermore, the threshold is still in controversy. For example, in the tion pattern, and aggravated mutation burden across multiple cancer
two clinical trials KEYNOTE-010 and KEYNOTE-042 investigating types [14].
pembrolizumab, an anti-PD-1 drug, versus chemotherapy for NSCLC, The association of ARID1A deficiency and high TMB is also de-
the threshold of PD-L1 is 50% in KEYNOTE-010, whereas it is 1% in monstrated by clinical studies. The largest study investigated 17,486
KEYNOTE-042 [20,21]. tubular gastrointestinal (GI) carcinomas and suggested that there was a
Accumulated evidences demonstrate that ARID1A deficiency cor- correlation between the selected DDR defects, including ARID1A, and a
relates with immunotherapy mechanically and clinically. In this review, high TMB in > 20% of cases [31]. Li et al. investigated three GI cancer
we will focus on the mechanisms underlying the association between genomics datasets and discovered that the elevated immune activity in
ARID1A deficiency and the efficacy of ICB, the predictive role of ARID1A-mutated GI cancers was linked to the higher tumor mutation
ARID1A deficiency for ICB, and ARID1A loss-vulnerable targeting burden and lower tumor aneuploidy level [32].
strategies, which exhibit potential synergy with ICB in cancer treat- It is interesting to observe that cancers with ARID1A deficiency
ment. commonly lack widespread genomic instability measured through copy
number alterations (CNAs) [6,33]. Paradoxically, since ARID1A inter-
2. Mechanisms underlying the correlation between ARID1A acts with topoisomerase Ⅱa (TOP2A) [34], which is critical for mitosis,
deficiency and immunotherapy ARID1A inactivation is supposed to cause large-scale genomic altera-
tions and aneuploidy. A recent study shed light on this issue, explaining
Mechanically, ARID1A deficiency correlates with the efficacy of that ARID1A inactivation impaired telomere cohesion, which selec-
immunotherapy by impairing mismatch repair (MMR), promoting tively eliminated gross chromosome aberrations by apoptosis [35].
tumor mutability, increasing the expression of PD-L1, and modulating More interestingly, although CNAs are positively associated with high
the tumor immune microenvironment (Fig. 1). TMB, increased somatic CNAs have been identified as immune sup-
pressors, and are linked to a worse response to anti-PD-1 or anti-CTLA-4
2.1. MMR therapy [36,37]. Thus, taken together, ARID1A inactivation, char-
acterized by elevated TMB and low CNAs, likely implies a very pro-
MMR is one of the well-recognized predictive biomarkers for im- mising response to ICB.
munotherapy. The tumor phenotype of microsatellites instability-high
(MSI-H) is characterized by any gene alterations in the MMR pathway, 2.3. PD-L1 expression
consisting of MSH2, MSH6, MLH1, and PMS2. MSI-H has been revealed
to contribute to Lynch syndrome and cancerous predisposition. Recent Engagement of the PD-L1 by PD1 leads to negative regulation of
preclinical researches described that MSI-H phenotype was correlated lymphocyte activation [38]. Their interaction is critical to control the
with high tumor mutation and neoantigen burden, increased expression balance of the global immune response in humans, which implies the
of PD-L1, and elevated tumor infiltrating lymphocyte (TIL), suggesting mechanism that ICB therapy performs antitumor function [39].
a pronounced response to ICB [22,23]. The results from the clinical trial Mounting evidences show that elevated PD-L1 expression is positively
(NCT01876511) supported the conclusion, which demonstrated that correlated with the response rate to ICB [40,41], although the corre-
the ORR was 53% for pembrolizumab in patients with advanced MMR- lation is not perfect and the underlying mechanisms remain largely
deficient cancers across 12 different tumor types, and the progression- unclear [42].
free survival (PFS) rate was 78% in MMR-deficient colorectal cancers Recent study discovered that ovarian tumors bearing ARID1A de-
[24,25]. Accordingly, the approval of pembrolizumab was expedited for ficiency presented increased PD-L1 expression in mouse models and
use in metastatic MMR-deficient/MSI-H solid cancers, without limits on patients’ samples [14]. Meanwhile, Kim et al. reported that positive
tumor origin. And nivolumab, was also approved for use in advanced expression of tumor PD-L1 was tightly associated with ARID1A defi-
colorectal cancers with MSI-H, alone or in combination with ipili- ciency in gastric cancer using a large cohort of 273 cases [43]. Con-
mumab, an anti-CTLA-4 drug. sistently, in gastrointestinal cancers, more highly expressed PD-L1 was
Initially, ARID1A deficiency was found to be much more prevalent found in ARID1A-mutated cases than in ARID1A-wildtype cases [32].
in the MSI-H phenotype in endometrial cancer and gastric adeno- Another study revealed that frequent frameshift mutations were ob-
carcinoma [26–28]. However, the underlying mechanisms were not served in ARID1A, RNF43, NF1, MSH6 and other genes in MSI-H gastric
fully determined. Subsequently, Bosse et al. described that ARID1A was cancer. Furthermore, they concluded that the numbers of frameshift
a causative gene instead of a target gene of MSI because of its role in the mutations, including ARID1A, correlated significantly with PD-L1 ex-
epigenetic silencing of the MLH1 gene in endometrial cancer [27]. A pression [44].

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Fig. 1. Mechanisms of the correlation between ARID1A-deficiency with immunotherapy. ARID1A deficiency impairs mismatch repair, promotes tumor
mutability, increases the expression of PD-L1, and modulates the tumor immune microenvironment, which underlie its correlation with the sensitivity to im-
munotherapy. ARID1A, the AT-rich interaction domain 1A; MMR, mismatch repair; SSB, single strand break; DSB, double strands break; BER, base-excision repair;
HR, homologous recombination; NHEJ, Non-homologous end joining; ATR, ataxia telangiectasia and rad3-related; ATM, ataxia telangiectasia-mutated; CHK1,
Checkpoint kinase 1; CHK2, Checkpoint kinase 2; IL-6, interleukin 6; TIL, tumor infiltrating lymphocyte; ICB, immune checkpoint blockade; PD-L1, programmed cell
death ligand 1; TMB, tumor mutation burden; MSI-H, microsatellite instability-high; TME, tumor microenvironment; PARP, poly (ADP-ribose) polymerase; PI3K,
phosphatidylinositol 3-kinase; AKT, protein kinase B.

The published mechanisms underlying the association between deficiency is linked to the increase of TILs, especially CD8+ T lym-
ARID1A deficiency and increased PD-L1 expression included: (1) phocytes, in immune TME, suggesting the vulnerability of tumors har-
ARID1A inactivation increased tumor PD-L1 expression through acti- boring ARID1A loss to immunotherapy.
vation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) Concomitantly, Chandler et al. displayed that in mouse models of
signaling in gastric cancer, which could be attenuated by a PI3K in- ovarian clear-cell carcinoma, coexistent ARID1A-PIK3CA mutations
hibitor, LY294002 [43]. (2) DSBs was reported to up-regulate the ex- were necessary for the induction of interleukin-6 (IL-6) on promoting
pression of PD-L1 in cancer cells, which required ATM/ATR/Chk1 ki- tumor genesis [55]. IL-6, predominantly secreted by T cells and mac-
nases [39]. As ARID1A has been revealed to interact with ATR to repair rophages, is known as a key cytokine in immune TME, which stimulates
DSBs efficiently [12], the DSBs induced by ARID1A deficiency are inflammatory responses, autoimmune disease, and tumorigenesis, via
speculated to elevate the expression of PD-L1. activation of signal transducer and activator of transcription 3 (STAT3)
through the JAK/STAT pathway [56]. IL-6 suppresses the antigen
presentation capacity of dendritic cells, and inhibits the activation of
2.4. Tumor microenvironment (TME) effector T cells through activating STAT3, indicating an im-
munosuppressive TME, which confers resistance to immunotherapy
It has been firmly established that the immune microenvironment is [57]. Therefore, blockade of the IL-6/STAT3 signaling pathway has
important to the antitumor immune response [45]. In TME, TILs, been described as an encouraging strategy to sensitize cancers for im-
especially effector CD8+ cytotoxic T lymphocytes (CTLs), are the major munotherapies through preclinical studies [58,59].
effector cells to promote the effective eradication of tumors [46,47]. Given the impact of ARID1A deficiency on the immune TME is
During this process, the tumor neoantigen-specific T cells are activated, multifaceted and profound, further exploration is warranted. The re-
and migrate into the tumor. Then, they produce effector functions to sults will be valuable to find new targets to improve the outcome of
eradicate tumor cells, and further develop stable immunological immunotherapy, as immunosuppressive TME is considered as the main
memory [48–51]. Evidence continues to emerge demonstrating that TIL cause of immunotherapy resistance [60].
could be used as a biomarker for the response to ICB, which was also
confirmed by the OAK study, a large-scale phase 3 clinical trial on
atezolizumab (an anti-PD-L1 drug) in lung cancer [52–54]. 3. Predictive role of ARID1A deficiency for immunotherapy
Shen et al. analyzed The Cancer Genome Atlas (TCGA) database,
and found that tumors with an increased TIL transcriptome signature The findings of the association between ARID1A inactivation and
had significantly reduced ARID1A expression, which was independent MMR, TMB, PD-L1 and TME, raise the possibility that ARID1A loss
from ARID1A-associated enhancer activity [9,14]. Notably, they also might serve as a predictive biomarker for ICB. Additionally, ARID1A is
discovered larger numbers of TILs in tumors of syngeneic mice, formed identified as a DDR-linked gene [12,61]. The deleterious DDR genes
by an ARID1A-deficient ovarian cancer cell line, compared with an alterations have been demonstrated to predict better response rates to
ARID1A-wild type cell line [14]. Additionally, through im- ICB, and are even correlated with an improved survival [62,63]. These
munohistochemistry analysis, they unveiled remarkable increase in the conclusions support the predictive role of ARID1A on immunotherapy.
protein cluster of differentiation 8 (CD8), a key CTLs marker, in Indeed, some explorations have been carried out in this field.
ARID1A-depleted orthotopic tumors, and in ovarian cancer patients’ Shen et al. demonstrated that in ARID1A-deficient tumors, ICB
specimens [14]. These conclusions support the view that ARID1A could restore antitumor immunity, and thereby inhibit tumor growth.

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They concluded that ARID1A inactivation could be used as a predictive intratumoral CD8+ T-cell infiltration and cytolytic activity, and is as-
biomarker for the response to ICB [14]. Another study of gastric cancer sociated with prominent and durable clinical response to ICIs [81–83].
reported that loss of ARID1A protein was the main oncogenic me- Multiple phase 3 clinical trials on the combinations of PARP inhibitors
chanism of PD-L1 expression, especially in the MSI-H group, suggesting with ICIs are ongoing now, with promising preliminary results [84,85].
ARID1A deficiency as a potential biomarker for PD-1/PD-L1 inhibition Beyond BRCA1/2, ARID1A-deficient tumors, characterized by an
[43]. attenuated capacity for DNA repair, have also demonstrated sensitivity
With regards to prognosis, ARID1A deficiency has been proposed as to PARP inhibitors [12]. However, PARP inhibitors often work par-
a prognostic biomarker for several cancers, although the converse still tially, and combination is a possible solution. Park et al. found that the
exists [64,65]. Interestingly, Buglioni et al. revealed that the activation combination of PARP inhibitor with ionizing radiation was selectively
of ARID1A and ATM affect the clinical significance of PD-L1 expression highly efficient in tumor cells with ARID1A deficiency from pre-clinical
in gastric cancer [61]. For the whole patients, PD-L1 expression did not evidences [86]. In terms of ICB, a phase 1 clinical trial (NCT03842228)
correlate with PFS or overall survival (OS). However, in the DDRoff combines olaparib (PARP inhibitor), copanlisib (PI3K inhibitor) and
subgroup (ARID1A mutations or negative pATM expression), positive durvalumab in patients with 25 genes mutation-selected advanced solid
expression of PD-L1 in tumor cells (PD-L1-TCs) was associated with tumors, including ARID1A, ATM, ATRX, BARD1, BRCA1, and BRCA2, to
better PFS and OS. Conversely, in the DDRon subgroup (concomitant evaluate the safety and anti-tumor activity. The trial is ongoing, and the
ARID1A wild-type and pATM expression), the PD-L1-TCs expression results are still unavailable.
had no correlation with PFS, whereas it correlated with worse OS [61].
The conclusions suggest that the combination of ARID1A loss with 4.2. PI3K/AKT
other biomarkers, such as PD-L1 expression, might predict the prog-
nosis more precisely. The PI3K/AKT pathway is commonly hyper-activated in cancers,
and controls most cellular processes, such as cell cycle, survival, me-
4. Potential synergistic targets to sensitize immunotherapy for tabolism, and genomic stability. Nevertheless, the antitumor capacity of
cancers harboring ARID1A deficiency PI3K inhibitors is disappointing [87]. Despite cancer cells, PI3K/AKT
pathway also affects the function of immune cells, and modulates TME.
Although the efficacy of ICB on cancer is encouraging, most cancer Inhibition of PI3K/AKT pathway has been manifested to enhance the
patients respond poorly to ICB. Since the safety profile of current ICB sensitivity to tumor-specific CD8+ T cell-mediated cytotoxicity, which
drugs is acceptable, the combined treatments of ICB with other thera- provided a rationale for the combination therapy of PI3K inhibitors
pies including chemotherapy, radiotherapy and targeting therapy are with ICB [88,89]. Originally, the co-existence of ARID1A deficiency
widely investigated. Virtually, pembrolizumab combined with che- with PI3K/AKT pathway activation was discovered, which promotes
motherapy, and durvalumab (an anti-PD-L1 antibody) following con- tumorigenesis [27,55]. Subsequently, tumors with ARID1A loss have
current chemo-radiotherapy have been approved as the standard been demonstrated sensitive to PI3K and AKT inhibitors [71,90]. Fur-
treatments for advanced NSCLC [66–68]. thermore, PI3K inhibitor combined with other treatment, containing
To date, based on the mutational status of ARID1A, targeting PARP inhibitor or radiotherapy has been validated as being effective in
therapies have been extensively studied in “synthetic lethality” manner, treating ARID1A deficient cancers [71,91]. For combination with ICB,
containing inhibition of poly (ADP-ribose) polymerase (PARP), PI3K/ currently, only the above-mentioned phase 1 clinical trial
AKT, ATR, enhancer of zeste homolog 2 (EZH2), and histone deacety- (NCT03842228) is ongoing.
lase 6 (HDAC6) [12,69–74]. In a phase 2 clinical trial (NCT04065269),
patients with gynecological cancers were selected based on the pre- 4.3. Others
sence of ARID1A loss to test the efficacy of the PARP inhibitor olaparib
combined with the ATR inhibitor AZD6738. Other targeting agents showing “synthetic lethality” with ARID1A
In fact, the inhibitors of PARP, PI3K/AKT, ATR, and EZH2, have deficiency, including the inhibitors of ATR and EZH2, have already
already been discovered to have potential synergy with immune been tested in combination with ICB in clinical trials (NCT02264678,
checkpoint inhibitors (ICIs). Currently, numerous clinical trials are NCT03334617, and NCT03854474), and preliminary antitumor capa-
ongoing to test the efficacy and toxicity of combined therapies with city is suggested. However, few preclinical or clinical studies explore
targeting agents and ICB. Due to the vulnerability of cancers harboring these combinations in ARID1A-mutation-selective cancers, which calls
ARID1A deficiency to indicated targeting agents and ICB, the combined for further exploration.
treatment seems to be much attractive (Fig. 2).
5. Conclusion
4.1. Poly (ADP-ribose) polymerase (PARP) inhibitors
ARID1A deficiency, which occurs with high frequency in cancer,
PARP inhibitors are designed for the treatment of homologous re- demonstrates vulnerability to ICB due to its association with MSI-H
combination (HR) deficient cancers, including dysfunction of BRCA1/2 phenotype, high TMB, increased expression of PD-L1, and immune-ac-
or other genes in the HR pathway, which is called “synthetic lethality”. tive TME. Initial published results support the predictive role of
Large-scale phase 3 clinical trials have demonstrated the efficacy of the ARID1A deficiency for ICB. Remarkably, the novel therapeutic tar-
PARP inhibitors for advanced ovarian cancer, breast cancer and pan- geting strategies, indicated by ARID1A deficiency, appear to synergize
creatic cancer mainly in patients with germline BRCA mutation with ICB promisingly. However, currently, only one clinical trial ad-
[75–77], which lead to the approval of PARP inhibitors by American dressing this issue is ongoing, and additional large-scale clinical trials
Food and Drug Administration (FDA). Nevertheless, the anti-tumor ef- are warranted.
ficacy of PARP inhibitors as monotherapy is limited, and only affords a Furthermore, despite ARID1A deficiency, genetic backgrounds of
PFS benefit of 2–4 months. Moreover, the OS benefit is not significant tumor should also be taken into account. A recent study reported that,
[78]. even in MMR-deficient tumors, genetic diversity influenced the anti-PD-
Currently, PARP inhibitors are among the most well established 1 immunotherapy response [92]. Thus, for cancers harboring ARID1A
targeting drugs combined with ICB. Mechanically, PARP inhibitors deficiency, diverse tumor settings and genetic backgrounds might also
elicit accumulated DNA damage, especially in HR-deficient circum- affect the optimal treatment options, such as single targeting drug or
stances, elevated cytosolic DNA and neoantigen load, which stimulate ICB, or the combined therapy, and even influence the combining timing
STING pathway and innate immune response [79,80], increase and sequences.

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Fig. 2. Mechanisms and potential combinations of therapeutic targeting agents with immune checkpoint blockade in ARID1A-deficient cancer. The impact
of ARID1A deficiency on immunity and cellular functions, indicates the vulnerability to immunotherapy and targeting agents, which show potential synergy with
each other and is warranted to be explored in the future. ARID1A, the AT-rich interaction domain 1A; PD-L1, programmed cell death ligand 1; TMB, tumor mutation
burden; MSI-H, microsatellite instability-high; TME, tumor microenvironment; PARP, poly (ADP-ribose) polymerase; ATR, ataxia telangiectasia and rad3-related;
PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; EZH2, enhancer of zeste homolog 2; HDAC6, histone deacetylase 6.

Collectively, due to the established correlation between ARID1A suppressor? Cancer Discov. 3 (2013) 35–43, https://doi.org/10.1158/2159-8290.
deficiency and ICB, further deep exploration on the impact of ARID1A cd-12-0361.
[3] O. Arnaud, F. Le Loarer, F. Tirode, Baffling pathologies: alterations of baf complexes
on tumor immunity, immune TME, response to immunotherapy, and in cancer, Cancer Lett. 419 (2018) 266–279, https://doi.org/10.1016/j.canlet.
optimal combination with immunotherapy, is of great clinical im- 2018.01.046.
portance. Hopefully, the results will facilitate efficient prediction of the [4] R.C. Wu, T.L. Wang, M. Shih Ie, The emerging roles of ARID1A in tumor suppres-
sion, Cancer Biol. Ther. 15 (2014) 655–664, https://doi.org/10.4161/cbt.28411.
response to immunotherapy, and development of more therapeutic [5] X. Wang, N.G. Nagl Jr., S. Flowers, D. Zweitzig, P.B. Dallas, E. Moran, Expression of
targeting strategies to overcome the narrow therapeutic window of p270 (ARID1A), a component of human SWI/SNF complexes, in human tumors, Int.
immunotherapy in the future. J. Cancer 112 (2004) 636, https://doi.org/10.1002/ijc.20450.
[6] K.C. Wiegand, S.P. Shah, O.M. Al-Agha, Y. Zhao, K. Tse, T. Zeng, J. Senz,
M.K. McConechy, M.S. Anglesio, S.E. Kalloger, W. Yang, A. Heravi-Moussavi,
Financial support R. Giuliany, C. Chow, J. Fee, A. Zayed, L. Prentice, N. Melnyk, G. Turashvili,
A.D. Delaney, J. Madore, S. Yip, A.W. McPherson, G. Ha, L. Bell, S. Fereday, A. Tam,
L. Galletta, P.N. Tonin, D. Provencher, D. Miller, S.J. Jones, R.A. Moore, G.B. Morin,
This study was sponsored by the Natural Science Foundation of
A. Oloumi, N. Boyd, S.A. Aparicio, M. Shih Ie, A.M. Mes-Masson, D.D. Bowtell,
Hubei Province (grant number 2015CFB541). M. Hirst, B. Gilks, M.A. Marra, D.G. Huntsman, ARID1A mutations in en-
dometriosis-associated ovarian carcinomas, N. Engl. J. Med. 363 (2010)
Author contributions 1532–1543, https://doi.org/10.1056/NEJMoa1008433.
[7] W. Wang, S.C. Friedland, B. Guo, M.R. O'Dell, W.B. Alexander, C.L. Whitney-Miller,
D. Agostini-Vulaj, A.R. Huber, J.R. Myers, J.M. Ashton, R.F. Dunne, L.A. Steiner,
GYH, WT, LiuY and LinY wrote the manuscript. GP reviewed, and A.F. Hezel, ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and
LinY revised the manuscript. regeneration and is a barrier to transformation and epithelial-mesenchymal tran-
sition in the pancreas, Gut 68 (2019) 1245–1258, https://doi.org/10.1136/gutjnl-
2017-315541.
Declaration of competing interest [8] S.C. Wang, I. Nassour, S. Xiao, S. Zhang, X. Luo, J. Lee, L. Li, X. Sun, L.H. Nguyen,
J.C. Chuang, L. Peng, S. Daigle, J. Shen, H. Zhu, SWI/SNF component ARID1A
restrains pancreatic neoplasia formation, Gut 68 (2019) 1259–1270, https://doi.
All the authors have no conflict of interests to disclose. org/10.1136/gutjnl-2017-315490.
[9] R. Mathur, B.H. Alver, A.K. San Roman, B.G. Wilson, X. Wang, A.T. Agoston,
Acknowledgements P.J. Park, R.A. Shivdasani, C.W. Roberts, ARID1A loss impairs enhancer-mediated
gene regulation and drives colon cancer in mice, Nat. Genet. 49 (2017) 296–302,
https://doi.org/10.1038/ng.3744.
We thank Editage (www.editage.com) for their linguistic assistance [10] X. Sun, S.C. Wang, Y. Wei, X. Luo, Y. Jia, L. Li, P. Gopal, M. Zhu, I. Nassour,
during the preparation of this manuscript. J.C. Chuang, T. Maples, C. Celen, L.H. Nguyen, L. Wu, S. Fu, W. Li, L. Hui, F. Tian,
Y. Ji, S. Zhang, M. Sorouri, T.H. Hwang, L. Letzig, L. James, Z. Wang, A.C. Yopp,
A.G. Singal, H. Zhu, Arid1a has context-dependent oncogenic and tumor suppressor
Appendix A. Supplementary data functions in liver cancer, Cancer Cell 32 (2017) 574–589, https://doi.org/10.1016/
j.ccell.2017.10.007 e576.
Supplementary data to this article can be found online at https:// [11] Y. Suryo Rahmanto, J.G. Jung, R.C. Wu, Y. Kobayashi, C.M. Heaphy, A.K. Meeker,
T.L. Wang, M. Shih Ie, Inactivating ARID1A tumor suppressor enhances TERT
doi.org/10.1016/j.canlet.2020.01.001. transcription and maintains telomere length in cancer cells, J. Biol. Chem. 291
(2016) 9690–9699, https://doi.org/10.1074/jbc.M115.707612.
References [12] J. Shen, Y. Peng, L. Wei, W. Zhang, L. Yang, L. Lan, P. Kapoor, Z. Ju, Q. Mo, M. Shih
Ie, I.P. Uray, X. Wu, P.H. Brown, X. Shen, G.B. Mills, G. Peng, ARID1A deficiency
impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors, Cancer
[1] B.G. Wilson, C.W. Roberts, SWI/SNF nucleosome remodellers and cancer, Nat. Rev. Discov. 5 (2015) 752–767, https://doi.org/10.1158/2159-8290.cd-14-0849.
Cancer 11 (2011) 481–492, https://doi.org/10.1038/nrc3068. [13] M. Trizzino, E. Barbieri, A. Petracovici, S. Wu, S.A. Welsh, T.A. Owens, S. Licciulli,
[2] J.N. Wu, C.W. Roberts, ARID1A mutations in cancer: another epigenetic tumor R. Zhang, A. Gardini, The tumor suppressor ARID1A controls global transcription

152
G. Hu, et al. Cancer Letters 473 (2020) 148–155

via pausing of RNA polymerase ii, Cell Rep. 23 (2018) 3933–3945, https://doi.org/ endometrial cancer, Mod. Pathol. 26 (2013) 1525–1535, https://doi.org/10.1038/
10.1016/j.celrep.2018.05.097. modpathol.2013.96.
[14] J. Shen, Z. Ju, W. Zhao, L. Wang, Y. Peng, Z. Ge, Z.D. Nagel, J. Zou, C. Wang, [28] K. Wang, J. Kan, S.T. Yuen, S.T. Shi, K.M. Chu, S. Law, T.L. Chan, Z. Kan, A.S. Chan,
P. Kapoor, X. Ma, D. Ma, J. Liang, S. Song, J. Liu, L.D. Samson, J.A. Ajani, G.M. Li, W.Y. Tsui, S.P. Lee, S.L. Ho, A.K. Chan, G.H. Cheng, P.C. Roberts, P.A. Rejto,
H. Liang, X. Shen, G.B. Mills, G. Peng, ARID1A deficiency promotes mutability and N.W. Gibson, D.J. Pocalyko, M. Mao, J. Xu, S.Y. Leung, Exome sequencing identifies
potentiates therapeutic antitumor immunity unleashed by immune checkpoint frequent mutation of ARID1A in molecular subtypes of gastric cancer, Nat. Genet.
blockade, Nat. Med. 24 (2018) 556–562, https://doi.org/10.1038/s41591-018- 43 (2011) 1219–1223, https://doi.org/10.1038/ng.982.
0012-z. [29] N. Ready, M.D. Hellmann, M.M. Awad, G.A. Otterson, M. Gutierrez, J.F. Gainor,
[15] S.L. Topalian, F.S. Hodi, J.R. Brahmer, S.N. Gettinger, D.C. Smith, D.F. McDermott, H. Borghaei, J. Jolivet, L. Horn, M. Mates, J. Brahmer, I. Rabinowitz, P.S. Reddy,
J.D. Powderly, R.D. Carvajal, J.A. Sosman, M.B. Atkins, P.D. Leming, D.R. Spigel, J. Chesney, J. Orcutt, D.R. Spigel, M. Reck, K.J. O'Byrne, L. Paz-Ares, W. Hu,
S.J. Antonia, L. Horn, C.G. Drake, D.M. Pardoll, L. Chen, W.H. Sharfman, K. Zerba, X. Li, B. Lestini, W.J. Geese, J.D. Szustakowski, G. Green, H. Chang,
R.A. Anders, J.M. Taube, T.L. McMiller, H. Xu, A.J. Korman, M. Jure-Kunkel, S.S. Ramalingam, First-line nivolumab plus ipilimumab in advanced non-small-cell
S. Agrawal, D. McDonald, G.D. Kollia, A. Gupta, J.M. Wigginton, M. Sznol, Safety, lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor
activity, and immune correlates of anti-PD-1 antibody in cancer, N. Engl. J. Med. mutational burden as biomarkers, J. Clin. Oncol. 37 (2019) 992–1000, https://doi.
366 (2012) 2443–2454, https://doi.org/10.1056/NEJMoa1200690. org/10.1200/jco.18.01042.
[16] F.S. Hodi, S.J. O'Day, D.F. McDermott, R.W. Weber, J.A. Sosman, J.B. Haanen, [30] High TMB predicts immunotherapy benefit, Cancer Discov. 8 (2018) 668, https://
R. Gonzalez, C. Robert, D. Schadendorf, J.C. Hassel, W. Akerley, A.J. van den doi.org/10.1158/2159-8290.cd-nb2018-048.
Eertwegh, J. Lutzky, P. Lorigan, J.M. Vaubel, G.P. Linette, D. Hogg, [31] A.R. Parikh, Y. He, T.S. Hong, R.B. Corcoran, J.W. Clark, D.P. Ryan, L. Zou,
C.H. Ottensmeier, C. Lebbe, C. Peschel, I. Quirt, J.I. Clark, J.D. Wolchok, J.S. Weber, D.T. Ting, D.V. Catenacci, J. Chao, M. Fakih, S.J. Klempner, J.S. Ross,
J. Tian, M.J. Yellin, G.M. Nichol, A. Hoos, W.J. Urba, Improved survival with ipi- G.M. Frampton, V.A. Miller, S.M. Ali, A.B. Schrock, Analysis of DNA damage re-
limumab in patients with metastatic melanoma, N. Engl. J. Med. 363 (2010) sponse gene alterations and tumor mutational burden across 17,486 tubular gas-
711–723, https://doi.org/10.1056/NEJMoa1003466. trointestinal carcinomas: implications for therapy, The Oncologist (2019), https://
[17] J.R. Brahmer, S.S. Tykodi, L.Q. Chow, W.J. Hwu, S.L. Topalian, P. Hwu, C.G. Drake, doi.org/10.1634/theoncologist.2019-0034.
L.H. Camacho, J. Kauh, K. Odunsi, H.C. Pitot, O. Hamid, S. Bhatia, R. Martins, [32] L. Li, M. Li, Z. Jiang, X. Wang, ARID1A mutations are associated with increased
K. Eaton, S. Chen, T.M. Salay, S. Alaparthy, J.F. Grosso, A.J. Korman, S.M. Parker, immune activity in gastrointestinal cancer, Cells (2019) 8, https://doi.org/10.
S. Agrawal, S.M. Goldberg, D.M. Pardoll, A. Gupta, J.M. Wigginton, Safety and 3390/cells8070678.
activity of anti-PD-L1 antibody in patients with advanced cancer, N. Engl. J. Med. [33] K.T. Kuo, T.L. Mao, X. Chen, Y. Feng, K. Nakayama, Y. Wang, R. Glas, M.J. Ma,
366 (2012) 2455–2465, https://doi.org/10.1056/NEJMoa1200694. R.J. Kurman, M. Shih Ie, T.L. Wang, DNA copy numbers profiles in affinity-purified
[18] S.J. Antonia, H. Borghaei, S.S. Ramalingam, L. Horn, J. De Castro Carpeno, ovarian clear cell carcinoma, Clin. Cancer Res. 16 (2010) 1997–2008, https://doi.
A. Pluzanski, M.A. Burgio, M. Garassino, L.Q.M. Chow, S. Gettinger, L. Crino, org/10.1158/1078-0432.ccr-09-2105.
D. Planchard, C. Butts, A. Drilon, J. Wojcik-Tomaszewska, G.A. Otterson, [34] E.C. Dykhuizen, D.C. Hargreaves, E.L. Miller, K. Cui, A. Korshunov, M. Kool,
S. Agrawal, A. Li, J.R. Penrod, J. Brahmer, Four-year survival with nivolumab in S. Pfister, Y.J. Cho, K. Zhao, G.R. Crabtree, Baf complexes facilitate decatenation of
patients with previously treated advanced non-small-cell lung cancer: a pooled DNA by topoisomerase iialpha, Nature 497 (2013) 624–627, https://doi.org/10.
analysis, Lancet Oncol. 20 (2019) 1395–1408, https://doi.org/10.1016/s1470- 1038/nature12146.
2045(19)30407-3. [35] B. Zhao, J. Lin, ARID1A promotes genomic stability through protecting telomere
[19] S. Gettinger, N.A. Rizvi, L.Q. Chow, H. Borghaei, J. Brahmer, N. Ready, D.E. Gerber, cohesion, Nat. Commun. 10 (2019) 4067, https://doi.org/10.1038/s41467-019-
F.A. Shepherd, S. Antonia, J.W. Goldman, R.A. Juergens, S.A. Laurie, F.E. Nathan, 12037-4.
Y. Shen, C.T. Harbison, M.D. Hellmann, Nivolumab monotherapy for first-line [36] T. Davoli, H. Uno, E.C. Wooten, S.J. Elledge, Tumor aneuploidy correlates with
treatment of advanced non-small-cell lung cancer, J. Clin. Oncol. 34 (2016) markers of immune evasion and with reduced response to immunotherapy, Science
2980–2987, https://doi.org/10.1200/jco.2016.66.9929. 355 (2017) 6322, https://doi.org/10.1126/science.aaf8399.
[20] R.S. Herbst, P. Baas, D.W. Kim, E. Felip, J.L. Perez-Gracia, J.Y. Han, J. Molina, [37] W. Roh, P.L. Chen, A. Reuben, C.N. Spencer, P.A. Prieto, J.P. Miller,
J.H. Kim, C.D. Arvis, M.J. Ahn, M. Majem, M.J. Fidler, G. de Castro Jr., M. Garrido, V. Gopalakrishnan, F. Wang, Z.A. Cooper, S.M. Reddy, C. Gumbs, Integrated mo-
G.M. Lubiniecki, Y. Shentu, E. Im, M. Dolled-Filhart, E.B. Garon, Pembrolizumab lecular analysis of tumor biopsies on sequential ctla-4 and PD-1 blockade reveals
versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell markers of response and resistance, Sci. Transl. Med. 9 (2017) 379, https://doi.org/
lung cancer (keynote-010): a randomised controlled trial, Lancet 387 (2016) 10.1126/scitranslmed.aah3560.
1540–1550, https://doi.org/10.1016/s0140-6736(15)01281-7. [38] G.J. Freeman, A.J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L.J. Fitz,
[21] T.S.K. Mok, Y.L. Wu, I. Kudaba, D.M. Kowalski, B.C. Cho, H.Z. Turna, G. Castro Jr., N. Malenkovich, T. Okazaki, M.C. Byrne, H.F. Horton, L. Fouser, L. Carter, V. Ling,
V. Srimuninnimit, K.K. Laktionov, I. Bondarenko, K. Kubota, G.M. Lubiniecki, M.R. Bowman, B.M. Carreno, M. Collins, C.R. Wood, T. Honjo, Engagement of the
J. Zhang, D. Kush, G. Lopes, Pembrolizumab versus chemotherapy for previously PD-1 immunoinhibitory receptor by a novel b7 family member leads to negative
untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung regulation of lymphocyte activation, J. Exp. Med. 192 (2000) 1027–1034, https://
cancer (keynote-042): a randomised, open-label, controlled, phase 3 trial, Lancet doi.org/10.1084/jem.192.7.1027.
393 (2019) 1819–1830, https://doi.org/10.1016/s0140-6736(18)32409-7. [39] H. Sato, A. Niimi, T. Yasuhara, DNA double-strand break repair pathway regulates
[22] Y.E. Maruvka, K.W. Mouw, R. Karlic, P. Parasuraman, A. Kamburov, P. Polak, PD-L1 expression in cancer cells, Nat. Commun. 8 (2017) 1751, https://doi.org/10.
N.J. Haradhvala, J.M. Hess, E. Rheinbay, Y. Brody, A. Koren, L.Z. Braunstein, 1038/s41467-017-01883-9.
A. D'Andrea, M.S. Lawrence, A. Bass, A. Bernards, F. Michor, G. Getz, Analysis of [40] M. Reck, D. Rodriguez-Abreu, A.G. Robinson, R. Hui, T. Csoszi, A. Fulop,
somatic microsatellite indels identifies driver events in human tumors, Nat. M. Gottfried, N. Peled, A. Tafreshi, S. Cuffe, M. O'Brien, S. Rao, K. Hotta,
Biotechnol. 35 (2017) 951–959, https://doi.org/10.1038/nbt.3966. M.A. Leiby, G.M. Lubiniecki, Y. Shentu, R. Rangwala, J.R. Brahmer, Pembrolizumab
[23] J. Galon, A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pages, versus chemotherapy for PD-L1-positive non-small-cell lung cancer, N. Engl. J. Med.
M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoue, P. Bruneval, 375 (2016) 1823–1833, https://doi.org/10.1056/NEJMoa1606774.
P.H. Cugnenc, Z. Trajanoski, W.H. Fridman, F. Pages, Type, density, and location of [41] E.B. Garon, N.A. Rizvi, R. Hui, N. Leighl, A.S. Balmanoukian, J.P. Eder, A. Patnaik,
immune cells within human colorectal tumors predict clinical outcome, Science 313 C. Aggarwal, M. Gubens, L. Horn, E. Carcereny, M.J. Ahn, E. Felip, J.S. Lee,
(2006) 1960–1964, https://doi.org/10.1126/science.1129139. M.D. Hellmann, O. Hamid, J.W. Goldman, J.C. Soria, M. Dolled-Filhart,
[24] D.T. Le, J.N. Durham, K.N. Smith, H. Wang, B.R. Bartlett, L.K. Aulakh, S. Lu, R.Z. Rutledge, J. Zhang, J.K. Lunceford, R. Rangwala, G.M. Lubiniecki, C. Roach,
H. Kemberling, C. Wilt, B.S. Luber, F. Wong, N.S. Azad, A.A. Rucki, D. Laheru, K. Emancipator, L. Gandhi, Pembrolizumab for the treatment of non-small-cell lung
R. Donehower, A. Zaheer, G.A. Fisher, T.S. Crocenzi, J.J. Lee, T.F. Greten, Duffy, cancer, N. Engl. J. Med. 372 (2015) 2018–2028, https://doi.org/10.1056/
G. Austin, K.K. Ciombor, A.D. Eyring, B.H. Lam, A. Joe, S.P. Kang, M. Holdhoff, NEJMoa1501824.
L. Danilova, L. Cope, C. Meyer, S. Zhou, R.M. Goldberg, D.K. Armstrong, [42] R.S. Herbst, J.C. Soria, M. Kowanetz, G.D. Fine, O. Hamid, M.S. Gordon,
K.M. Bever, A.N. Fader, J. Taube, F. Housseau, D. Spetzler, N.Q. Xiao, D.M. Pardoll, J.A. Sosman, D.F. McDermott, J.D. Powderly, S.N. Gettinger, H.E. Kohrt, L. Horn,
N. Papadopoulos, K.W. Kinzler, J.R. Eshleman, B. Vogelstein, R.A. Anders, L.A. Diaz D.P. Lawrence, S. Rost, M. Leabman, Y. Xiao, A. Mokatrin, H. Koeppen, P.S. Hegde,
Jr., Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, I. Mellman, D.S. Chen, F.S. Hodi, Predictive correlates of response to the anti-PD-L1
Science 357 (2017) 409–413, https://doi.org/10.1126/science.aan6733. antibody mpdl3280a in cancer patients, Nature 515 (2014) 563–567, https://doi.
[25] D.T. Le, J.N. Uram, H. Wang, B.R. Bartlett, H. Kemberling, A.D. Eyring, A.D. Skora, org/10.1038/nature14011.
B.S. Luber, N.S. Azad, D. Laheru, B. Biedrzycki, R.C. Donehower, A. Zaheer, [43] Y.B. Kim, J.M. Ahn, W.J. Bae, C.O. Sung, D. Lee, Functional loss of ARID1A is
G.A. Fisher, T.S. Crocenzi, J.J. Lee, S.M. Duffy, R.M. Goldberg, A. de la Chapelle, tightly associated with high PD-L1 expression in gastric cancer, Int. J. Cancer 145
M. Koshiji, F. Bhaijee, T. Huebner, R.H. Hruban, L.D. Wood, N. Cuka, D.M. Pardoll, (2019) 916–926, https://doi.org/10.1002/ijc.32140.
N. Papadopoulos, K.W. Kinzler, S. Zhou, T.C. Cornish, J.M. Taube, R.A. Anders, [44] J. Cho, Y.H. Chang, Y.J. Heo, S. Kim, N.K. Kim, J.O. Park, W.K. Kang, J. Lee,
J.R. Eshleman, B. Vogelstein, L.A. Diaz Jr., PD-1 blockade in tumors with mismatch- K.M. Kim, Four distinct immune microenvironment subtypes in gastric adeno-
repair deficiency, N. Engl. J. Med. 372 (2015) 2509–2520, https://doi.org/10. carcinoma with special reference to microsatellite instability, ESMO Open 3 (2018)
1056/NEJMoa1500596. e000326, , https://doi.org/10.1136/esmoopen-2018-000326.
[26] N. Han, M.A. Kim, H.S. Lee, W.H. Kim, Loss of ARID1A expression is related to [45] R. Saleh, E. Elkord, Acquired resistance to cancer immunotherapy: role of tumor-
gastric cancer progression, epstein-barr virus infection, and mismatch repair defi- mediated immunosuppression, Semin. Cancer Biol. (2019), https://doi.org/10.
ciency, Appl. Immunohistochem. Mol. Morphol. 24 (2016) 320–325, https://doi. 1016/j.semcancer.2019.07.017.
org/10.1097/pai.0000000000000199. [46] N. Yatim, S. Cullen, M.L. Albert, Dying cells actively regulate adaptive immune
[27] T. Bosse, N.T. ter Haar, L.M. Seeber, P.J. v Diest, F.J. Hes, H.F. Vasen, R.A. Nout, responses, Nat. Rev. Immunol. 17 (2017) 262–275, https://doi.org/10.1038/nri.
C.L. Creutzberg, H. Morreau, V.T. Smit, Loss of ARID1A expression and its re- 2017.9.
lationship with PI3K-akt pathway alterations, TP53 and microsatellite instability in [47] D.C. Tscharke, N.P. Croft, P.C. Doherty, N.L. La Gruta, Sizing up the key

153
G. Hu, et al. Cancer Letters 473 (2020) 148–155

determinants of the cd8(+) t cell response, Nat. Rev. Immunol. 15 (2015) 705–716, marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial can-
https://doi.org/10.1038/nri3905. cers, J. Clin. Oncol. 36 (2018) 1685–1694, https://doi.org/10.1200/jco.2017.75.
[48] P.C. Tumeh, C.L. Harview, J.H. Yearley, I.P. Shintaku, E.J. Taylor, L. Robert, 7740.
B. Chmielowski, M. Spasic, G. Henry, V. Ciobanu, A.N. West, M. Carmona, [64] C. Luchini, N. Veronese, M. Solmi, H. Cho, J.H. Kim, A. Chou, A.J. Gill, S.F. Faraj,
C. Kivork, E. Seja, G. Cherry, A.J. Gutierrez, T.R. Grogan, C. Mateus, G. Tomasic, A. Chaux, G.J. Netto, K. Nakayama, S. Kyo, S.Y. Lee, D.W. Kim, G.M. Yousef,
J.A. Glaspy, R.O. Emerson, H. Robins, R.H. Pierce, D.A. Elashoff, C. Robert, A. Scorilas, G.S. Nelson, M. Kobel, S.E. Kalloger, D.F. Schaeffer, H.B. Yan, F. Liu,
A. Ribas, PD-1 blockade induces responses by inhibiting adaptive immune re- Y. Yokoyama, X. Zhang, D. Pang, Z. Lichner, G. Sergi, E. Manzato, P. Capelli,
sistance, Nature 515 (2014) 568–571, https://doi.org/10.1038/nature13954. L.D. Wood, A. Scarpa, C.U. Correll, Prognostic role and implications of mutation
[49] J.M. Zaretsky, A. Garcia-Diaz, D.S. Shin, H. Escuin-Ordinas, W. Hugo, S. Hu- status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-
Lieskovan, D.Y. Torrejon, G. Abril-Rodriguez, S. Sandoval, L. Barthly, J. Saco, analysis, Oncotarget 6 (2015) 39088–39097, https://doi.org/10.18632/oncotarget.
B. Homet Moreno, R. Mezzadra, B. Chmielowski, K. Ruchalski, I.P. Shintaku, 5142.
P.J. Sanchez, C. Puig-Saus, G. Cherry, E. Seja, X. Kong, J. Pang, B. Berent-Maoz, [65] L. Yang, S. Wei, R. Zhao, Y. Wu, H. Qiu, H. Xiong, Loss of ARID1A expression
B. Comin-Anduix, T.G. Graeber, P.C. Tumeh, T.N. Schumacher, R.S. Lo, A. Ribas, predicts poor survival prognosis in gastric cancer: a systematic meta-analysis from
Mutations associated with acquired resistance to PD-1 blockade in melanoma, N. 14 studies, Sci. Rep. 6 (2016) 28919, , https://doi.org/10.1038/srep28919.
Engl. J. Med. 375 (2016) 819–829, https://doi.org/10.1056/NEJMoa1604958. [66] S.J. Antonia, A. Villegas, D. Daniel, D. Vicente, S. Murakami, R. Hui, T. Yokoi,
[50] E.J. Wherry, M. Kurachi, Molecular and cellular insights into t cell exhaustion, Nat. A. Chiappori, K.H. Lee, M. de Wit, B.C. Cho, M. Bourhaba, X. Quantin, T. Tokito,
Rev. Immunol. 15 (2015) 486–499, https://doi.org/10.1038/nri3862. T. Mekhail, D. Planchard, Y.C. Kim, C.S. Karapetis, S. Hiret, G. Ostoros, K. Kubota,
[51] A. Ribas, D.S. Shin, J. Zaretsky, J. Frederiksen, A. Cornish, E. Avramis, E. Seja, J.E. Gray, L. Paz-Ares, J. de Castro Carpeno, C. Wadsworth, G. Melillo, H. Jiang,
C. Kivork, J. Siebert, P. Kaplan-Lefko, X. Wang, B. Chmielowski, J.A. Glaspy, Y. Huang, P.A. Dennis, M. Ozguroglu, Durvalumab after chemoradiotherapy in
P.C. Tumeh, T. Chodon, D. Pe'er, B. Comin-Anduix, PD-1 blockade expands in- stage iii non-small-cell lung cancer, N. Engl. J. Med. 377 (2017) 1919–1929,
tratumoral memory t cells, Cancer Immunol Res 4 (2016) 194–203, https://doi.org/ https://doi.org/10.1056/NEJMoa1709937.
10.1158/2326-6066.cir-15-0210. [67] S.J. Antonia, A. Villegas, D. Daniel, D. Vicente, S. Murakami, R. Hui, T. Kurata,
[52] Y. Geng, Y. Shao, W. He, W. Hu, Y. Xu, J. Chen, C. Wu, J. Jiang, Prognostic role of A. Chiappori, K.H. Lee, M. de Wit, B.C. Cho, M. Bourhaba, X. Quantin, T. Tokito,
tumor-infiltrating lymphocytes in lung cancer: a meta-analysis, Cell. Physiol. T. Mekhail, D. Planchard, Y.C. Kim, C.S. Karapetis, S. Hiret, G. Ostoros, K. Kubota,
Biochem. 37 (2015) 1560–1571, https://doi.org/10.1159/000438523. J.E. Gray, L. Paz-Ares, J. de Castro Carpeno, C. Faivre-Finn, M. Reck,
[53] Y. Simoni, E. Becht, M. Fehlings, C.Y. Loh, S.L. Koo, K.W.W. Teng, J.P.S. Yeong, J. Vansteenkiste, D.R. Spigel, C. Wadsworth, G. Melillo, M. Taboada, P.A. Dennis,
R. Nahar, T. Zhang, H. Kared, K. Duan, N. Ang, M. Poidinger, Y.Y. Lee, A. Larbi, M. Ozguroglu, Overall survival with durvalumab after chemoradiotherapy in stage
A.J. Khng, E. Tan, C. Fu, R. Mathew, M. Teo, W.T. Lim, C.K. Toh, B.H. Ong, T. Koh, iii nsclc, N. Engl. J. Med. 379 (2018) 2342–2350, https://doi.org/10.1056/
A.M. Hillmer, A. Takano, T.K.H. Lim, E.H. Tan, W. Zhai, D.S.W. Tan, I.B. Tan, NEJMoa1809697.
E.W. Newell, Bystander cd8(+) t cells are abundant and phenotypically distinct in [68] L. Gandhi, D. Rodriguez-Abreu, S. Gadgeel, E. Esteban, E. Felip, F. De Angelis,
human tumour infiltrates, Nature 557 (2018) 575–579, https://doi.org/10.1038/ M. Domine, P. Clingan, M.J. Hochmair, S.F. Powell, S.Y. Cheng, H.G. Bischoff,
s41586-018-0130-2. N. Peled, F. Grossi, R.R. Jennens, M. Reck, R. Hui, E.B. Garon, M. Boyer, B. Rubio-
[54] A. Rittmeyer, F. Barlesi, D. Waterkamp, K. Park, F. Ciardiello, J. von Pawel, Viqueira, S. Novello, T. Kurata, J.E. Gray, J. Vida, Z. Wei, J. Yang, H. Raftopoulos,
S.M. Gadgeel, T. Hida, D.M. Kowalski, M.C. Dols, D.L. Cortinovis, J. Leach, M.C. Pietanza, M.C. Garassino, Pembrolizumab plus chemotherapy in metastatic
J. Polikoff, C. Barrios, F. Kabbinavar, O.A. Frontera, F. De Marinis, H. Turna, non-small-cell lung cancer, N. Engl. J. Med. 378 (2018) 2078–2092, https://doi.
J.S. Lee, M. Ballinger, M. Kowanetz, P. He, D.S. Chen, A. Sandler, D.R. Gandara, org/10.1056/NEJMoa1801005.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell [69] B.G. Bitler, N. Fatkhutdinov, R. Zhang, Potential therapeutic targets in ARID1A-
lung cancer (oak): a phase 3, open-label, multicentre randomised controlled trial, mutated cancers, Expert Opin. Ther. Targets 19 (2015) 1419–1422, https://doi.org/
Lancet 389 (2017) 255–265, https://doi.org/10.1016/s0140-6736(16)32517-x. 10.1517/14728222.2015.1062879.
[55] R.L. Chandler, J.S. Damrauer, J.R. Raab, J.C. Schisler, M.D. Wilkerson, J.P. Didion, [70] C.T. Williamson, R. Miller, H.N. Pemberton, S.E. Jones, J. Campbell, A. Konde,
J. Starmer, D. Serber, D. Yee, J. Xiong, D.B. Darr, F. Pardo-Manuel de Villena, N. Badham, R. Rafiq, R. Brough, A. Gulati, C.J. Ryan, Atr inhibitors as a synthetic
W.Y. Kim, T. Magnuson, Coexistent ARID1A-pik3ca mutations promote ovarian lethal therapy for tumours deficient in ARID1A, Nat. Commun. 7 (2016) 13837, ,
clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling, https://doi.org/10.1038/ncomms13837.
Nat. Commun. 6 (2015) 6118, https://doi.org/10.1038/ncomms7118. [71] E.P. Samartzis, K. Gutsche, K.J. Dedes, D. Fink, M. Stucki, P. Imesch, Loss of
[56] C.A. Hunter, S.A. Jones, Il-6 as a keystone cytokine in health and disease, Nat. ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition, Oncotarget
Immunol. 16 (2015) 448–457, https://doi.org/10.1038/ni.3153. 5 (2014) 5295–5303, https://doi.org/10.18632/oncotarget.2092.
[57] H. Kitamura, Y. Ohno, Y. Toyoshima, J. Ohtake, S. Homma, H. Kawamura, [72] B.G. Bitler, K.M. Aird, A. Garipov, H. Li, M. Amatangelo, A.V. Kossenkov,
N. Takahashi, A. Taketomi, Interleukin-6/stat3 signaling as a promising target to D.C. Schultz, Q. Liu, M. Shih Ie, J.R. Conejo-Garcia, D.W. Speicher, R. Zhang,
improve the efficacy of cancer immunotherapy, Cancer Sci. 108 (2017) 1947–1952, Synthetic lethality by targeting ezh2 methyltransferase activity in ARID1A-mutated
https://doi.org/10.1111/cas.13332. cancers, Nat. Med. 21 (2015) 231–238, https://doi.org/10.1038/nm.3799.
[58] H. Tsukamoto, K. Fujieda, A. Miyashita, S. Fukushima, T. Ikeda, Y. Kubo, S. Senju, [73] S. Gupta, D.J. Albertson, T.J. Parnell, A. Butterfield, A. Weston, L.M. Pappas,
H. Ihn, Y. Nishimura, H. Oshiumi, Combined blockade of IL6 and PD-1/PD-L1 B. Dalley, J.M. O'Shea, W.T. Lowrance, B.R. Cairns, J.D. Schiffman, Histone
signaling abrogates mutual regulation of their immunosuppressive effects in the Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced
tumor microenvironment, Cancer Res. 78 (2018) 5011–5022, https://doi.org/10. Urothelial Carcinoma 18 (2019), pp. 185–195, https://doi.org/10.1158/1535-
1158/0008-5472.can-18-0118. 7163.mct-17-0957.
[59] T.A. Mace, R. Shakya, J.R. Pitarresi, B. Swanson, C.W. McQuinn, S. Loftus, [74] T. Fukumoto, N. Fatkhutdinov, J.A. Zundell, E.N. Tcyganov, T. Nacarelli,
E. Nordquist, Z. Cruz-Monserrate, L. Yu, G. Young, X. Zhong, T.A. Zimmers, S. Karakashev, S. Wu, Q. Liu, D.I. Gabrilovich, R. Zhang, HDAC6 inhibition sy-
M.C. Ostrowski, T. Ludwig, M. Bloomston, T. Bekaii-Saab, G.B. Lesinski, Il-6 and nergizes with anti-PD-L1 therapy in ARID1A-inactivated ovarian cancer, Cancer
PD-L1 antibody blockade combination therapy reduces tumour progression in Res. 79 (2019) 5482–5489, https://doi.org/10.1158/0008-5472.can-19-1302.
murine models of pancreatic cancer, Gut 67 (2018) 320–332, https://doi.org/10. [75] K. Moore, N. Colombo, G. Scambia, B.G. Kim, A. Oaknin, M. Friedlander,
1136/gutjnl-2016-311585. A. Lisyanskaya, A. Floquet, A. Leary, G.S. Sonke, C. Gourley, S. Banerjee, A. Oza,
[60] H. Phuengkham, L. Ren, I.W. Shin, Y.T. Lim, Nanoengineered Immune Niches for A. Gonzalez-Martin, C. Aghajanian, W. Bradley, C. Mathews, J. Liu, E.S. Lowe,
Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing R. Bloomfield, P. DiSilvestro, Maintenance olaparib in patients with newly diag-
Cancer Immunotherapy 31 (2019) e1803322, , https://doi.org/10.1002/adma. nosed advanced ovarian cancer, N. Engl. J. Med. 379 (2018) 2495–2505, https://
201803322. doi.org/10.1056/NEJMoa1810858.
[61] S. Buglioni, E. Melucci, F. Sperati, M. Pallocca, I. Terrenato, F. De Nicola, [76] M. Robson, S.A. Im, E. Senkus, B. Xu, S.M. Domchek, N. Masuda, S. Delaloge, W. Li,
F. Goeman, B. Casini, C.A. Amoreo, E. Gallo, M.G. Diodoro, E. Pescarmona, P. Vici, N. Tung, A. Armstrong, W. Wu, C. Goessl, S. Runswick, P. Conte, Olaparib for
D. Sergi, L. Pizzuti, L. Di Lauro, M. Mazzotta, M. Barba, M. Fanciulli, I. Vitale, R. De metastatic breast cancer in patients with a germline BRCA mutation, N. Engl. J.
Maria, G. Ciliberto, M. Maugeri-Sacca, The clinical significance of PD-L1 in ad- Med. 377 (2017) 523–533, https://doi.org/10.1056/NEJMoa1706450.
vanced gastric cancer is dependent on ARID1A mutations and atm expression, [77] T. Golan, P. Hammel, M. Reni, E. Van Cutsem, T. Macarulla, M.J. Hall, J.O. Park,
OncoImmunology 7 (2018) e1457602, , https://doi.org/10.1080/2162402x.2018. D. Hochhauser, D. Arnold, D.Y. Oh, A. Reinacher-Schick, G. Tortora, H. Algul,
1457602. E.M. O'Reilly, D. McGuinness, K.Y. Cui, K. Schlienger, G.Y. Locker, H.L. Kindler,
[62] A.G. Robertson, J. Kim, H. Al-Ahmadie, J. Bellmunt, G. Guo, A.D. Cherniack, Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, N.
T. Hinoue, P.W. Laird, K.A. Hoadley, R. Akbani, M.A.A. Castro, E.A. Gibb, Engl. J. Med. 381 (2019) 317–327, https://doi.org/10.1056/NEJMoa1903387.
R.S. Kanchi, D.A. Gordenin, S.A. Shukla, F. Sanchez-Vega, D.E. Hansel, [78] T. Prasanna, F. Wu, K.K. Khanna, D. Yip, L. Malik, J.E. Dahlstrom, S. Rao,
B.A. Czerniak, V.E. Reuter, X. Su, B. de Sa Carvalho, V.S. Chagas, K.L. Mungall, Optimizing poly (adp-ribose) polymerase inhibition through combined epigenetic
S. Sadeghi, C.S. Pedamallu, Y. Lu, L.J. Klimczak, J. Zhang, C. Choo, A.I. Ojesina, and immunotherapy, Cancer Sci. 109 (2018) 3383–3392, https://doi.org/10.1111/
S. Bullman, K.M. Leraas, T.M. Lichtenberg, C.J. Wu, N. Schultz, G. Getz, cas.13799.
M. Meyerson, G.B. Mills, D.J. McConkey, J.N. Weinstein, D.J. Kwiatkowski, [79] L. Corrales, S.M. McWhirter, T.W. Dubensky Jr., T.F. Gajewski, The host STING
S.P. Lerner, Comprehensive molecular characterization of muscle-invasive bladder pathway at the interface of cancer and immunity, J. Clin. Investig. 126 (2016)
cancer, Cell 171 (2017) 540–556, https://doi.org/10.1016/j.cell.2017.09.007 2404–2411, https://doi.org/10.1172/jci86892.
e525. [80] L. Corrales, T.F. Gajewski, Molecular pathways: targeting the stimulator of inter-
[63] M.Y. Teo, K. Seier, I. Ostrovnaya, A.M. Regazzi, B.E. Kania, M.M. Moran, feron genes (STING) in the immunotherapy of cancer, Clin. Cancer Res. 21 (2015)
C.K. Cipolla, M.J. Bluth, J. Chaim, H. Al-Ahmadie, A. Snyder, M.I. Carlo, D.B. Solit, 4774–4779, https://doi.org/10.1158/1078-0432.ccr-15-1362.
M.F. Berger, S. Funt, J.D. Wolchok, G. Iyer, D.F. Bajorin, M.K. Callahan, [81] T.N. Schumacher, R.D. Schreiber, Neoantigens in cancer immunotherapy, Science
J.E. Rosenberg, Alterations in DNA damage response and repair genes as potential 348 (2015) 69–74, https://doi.org/10.1126/science.aaa4971.

154
G. Hu, et al. Cancer Letters 473 (2020) 148–155

[82] N. McGranahan, A.J. Furness, R. Rosenthal, S. Ramskov, R. Lyngaa, S.K. Saini, vulnerability to combined ionizing radiation and PARP inhibitor therapy, Clin.
M. Jamal-Hanjani, G.A. Wilson, N.J. Birkbak, C.T. Hiley, T.B. Watkins, S. Shafi, Cancer Res. 25 (2019) 5584–5594, https://doi.org/10.1158/1078-0432.ccr-18-
N. Murugaesu, R. Mitter, A.U. Akarca, J. Linares, T. Marafioti, J.Y. Henry, E.M. Van 4222.
Allen, D. Miao, B. Schilling, D. Schadendorf, L.A. Garraway, V. Makarov, N.A. Rizvi, [87] K. Okkenhaug, M. Graupera, B. Vanhaesebroeck, Targeting PI3K in cancer: impact
A. Snyder, M.D. Hellmann, T. Merghoub, J.D. Wolchok, S.A. Shukla, C.J. Wu, on tumor cells, their protective stroma, angiogenesis, and immunotherapy, Cancer
K.S. Peggs, T.A. Chan, S.R. Hadrup, S.A. Quezada, C. Swanton, Clonal neoantigens Discov. 6 (2016) 1090–1105, https://doi.org/10.1158/2159-8290.cd-16-0716.
elicit t cell immunoreactivity and sensitivity to immune checkpoint blockade, [88] K.H. Noh, T.H. Kang, J.H. Kim, S.I. Pai, K.Y. Lin, C.F. Hung, T.C. Wu, T.W. Kim,
Science 351 (2016) 1463–1469, https://doi.org/10.1126/science.aaf1490. Activation of akt as a mechanism for tumor immune evasion, Mol. Ther. 17 (2009)
[83] G.N. Barber, STING: infection, inflammation and cancer, Nat. Rev. Immunol. 15 439–447, https://doi.org/10.1038/mt.2008.255.
(2015) 760–770, https://doi.org/10.1038/nri3921. [89] J.S. O'Donnell, D. Massi, M.W.L. Teng, M. Mandala, PI3K-AKT-mtor inhibition in
[84] P.A. Konstantinopoulos, S.E. Waggoner, G.A. Vidal, M.M. Mita, G.F. Fleming, cancer immunotherapy, redux, Semin. Cancer Biol. 48 (2018) 91–103, https://doi.
R.W. Holloway, Topacio/keynote-162 (nct02657889): a phase 1/2 study of nir- org/10.1016/j.semcancer.2017.04.015.
aparib + pembrolizumab in patients (pts) with advanced triple-negative breast [90] D. Lee, E.J. Yu, I.H. Ham, H. Hur, Y.S. Kim, AKT inhibition is an effective treatment
cancer or recurrent ovarian cancer (ROC)—results from ROC cohort, J. Clin. Oncol. strategy in ARID1A-deficient gastric cancer cells, OncoTargets Ther. 10 (2017)
36 (suppl) (2018) A106 [abstract]. 4153–4159, https://doi.org/10.2147/ott.s139664.
[85] A. Thomas, R. Vilimas, C. Trindade, R. Erwin-Cohen, N. Roper, L. Xi, [91] L. Yang, G. Yang, Y. Ding, Y. Dai, S. Xu, Q. Guo, A. Xie, G. Hu, Inhibition of PI3K/
V. Krishnasamy, E. Levy, A. Mammen, S. Nichols, Y. Chen, V. Velcheti, F. Yin, AKT signaling pathway radiosensitizes pancreatic cancer cells with ARID1A defi-
E. Szabo, Y. Pommier, S.M. Steinberg, J.B. Trepel, M. Raffeld, H.A. Young, J. Khan, ciency in vitro, J. Cancer 9 (2018) 890–900, https://doi.org/10.7150/jca.21306.
S. Hewitt, J.M. Lee, Durvalumab in combination with olaparib in patients with [92] R. Mandal, R.M. Samstein, K.W. Lee, J.J. Havel, H. Wang, C. Krishna, E.Y. Sabio,
relapsed SCLC: results from a phase ii study, J. Thorac. Oncol. (2019), https://doi. V. Makarov, F. Kuo, P. Blecua, A.T. Ramaswamy, J.N. Durham, B. Bartlett, X. Ma,
org/10.1016/j.jtho.2019.04.026. R. Srivastava, S. Middha, A. Zehir, J.F. Hechtman, L.G. Morris, N. Weinhold,
[86] Y. Park, M.H. Chui, Y. Suryo Rahmanto, Z.C. Yu, R.A. Shamanna, M.A. Bellani, N. Riaz, D.T. Le, L.A. Diaz Jr., T.A. Chan, Genetic diversity of tumors with mismatch
S. Gaillard, A. Ayhan, A. Viswanathan, M.M. Seidman, S. Franco, A.K.L. Leung, repair deficiency influences anti-PD-1 immunotherapy response, Science 364
V.A. Bohr, I.M. Shih, T.L. Wang, Loss of ARID1A in tumor cells renders selective (2019) 485–491, https://doi.org/10.1126/science.aau0447.

155