Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy
Jing Li, … , Arul M. Chinnaiyan, Weiping Zou
Jing Li, … , Arul M. Chinnaiyan, Weiping Zou
Published February 6, 2020
Citation Information: J Clin Invest. 2020;130(5):2712-2726. https://doi.org/10.1172/JCI134402.
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Research Article Immunology

Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy

Abstract

Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BRG/BRM-associated factor chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to IFN-responsive genes, impaired IFN gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies and in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.

Authors

Jing Li, Weichao Wang, Yajia Zhang, Marcin Cieślik, Jipeng Guo, Mengyao Tan, Michael D. Green, Weimin Wang, Heng Lin, Wei Li, Shuang Wei, Jiajia Zhou, Gaopeng Li, Xiaojun Jing, Linda Vatan, Lili Zhao, Benjamin Bitler, Rugang Zhang, Kathleen R. Cho, Yali Dou, Ilona Kryczek, Timothy A. Chan, David Huntsman, Arul M. Chinnaiyan, Weiping Zou

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Figure 7

ARID1A gene status affects checkpoint therapy.

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ARID1A gene status affects checkpoint therapy. (A–D) Effect of ARID1A on...
(A–D) Effect of ARID1A on anti–PD-L1 therapy in MC38-bearing mice. Mice bearing shARID1A and vector MC38 tumors were treated with anti–PD-L1 or isotype. (A) Tumor volume was monitored. (B–D) Tumor IL-2+CD4+ (B), IFN-γ+CD8+ (C), and Adpgk-specific CD8+ (D) T cells were analyzed on day 25. One of 6 experiments. Mean ± SD, Mann-Whitney U test. (E) Effect of ARID1A mutations on immunotherapeutic efficacy in metastatic melanoma patients with (n = 14) or without (n = 268) ARID1A C-terminal mutations. Response rate is shown in patients with clinical benefits (CB, n = 109), including complete response (CR), partial response (PR), and stable disease (SD), and progressive patients (PD) (nonclinical benefits, NCB, n = 173). One-sided χ2 test, P = 0.0326. (F and G) Effect of ARID1A levels on immunotherapeutic efficacy in 52 metastatic melanoma patients with 47 WT and 5 mutated ARID1A. (F) Response rate is shown in patients with low (n = 26) and high (n = 26) ARID1A expression. ARID1A-mutated patients were placed in the ARID1A low group. Two-sided χ2 test, P = 0.0125. (G) Response status with corresponding specific ARID1A fragments per kilobase of transcript per million mapped reads is shown. (H) Effect of tumor mutation load (TMB) on immunotherapeutic efficacy. WT ARID1A melanoma patients were divided into high-TMB (n = 29) and low-TMB (n = 22) groups. Response rate was analyzed in patients with high and low TMB. In high-TMB group, 14 and 15 patients expressed, respectively, low and high ARID1A. In low-TMB group, 11 and 11 patients expressed, respectively, low and high ARID1A. Cutoff value: 100 mutations (31). Two-sided χ2 test, P < 0.0001. (I) Effect of anti–PD-1 on biological pathways in melanoma patients. Differential gene expression between CB and NCB groups was entered for DAVID pathway analysis (65). *P < 0.05; **P < 0.01.