Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy
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
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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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 4

ARID1A biochemically interacts with EZH2.

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ARID1A biochemically interacts with EZH2. (A) Interaction between ARID1A...
(A) Interaction between ARID1A and EZH2 in primary high-grade serous ovarian cancer cells (OC8). Endogenous EZH2 was immunoprecipitated with anti-EZH2 and ARID1A was probed with Western blot. One of 3 is shown. (B) Schematic representation of the full-length ARID1A (ARID1A A) and multiple ARID1A mutants (ARID1A B, C, D). The full-length ARID1A and mutants were used for co-interaction analyses. (C) Interaction between ARID1A and EZH2. Myc-EZH2 and Flag-ARID1A full-length and mutants were ectopically expressed in HEK293T cells, followed by EZH2 immunoprecipitations and immunoblotting with Flag and EZH2 antibodies. Inputs are shown in bottom panels. One of 3 is shown. (D) In vitro binding of ARID1A to EZH2. Recombinant His-ARID1A C-terminal DUF 3518 domain partial protein (AA1976-2231) was incubated with GST-EZH2 recombinant protein, followed by His tag pulldown and immunoblotting with GST antibody. Inputs are shown in bottom panels. One of 3 is shown. (E) R1989* hotspot mutation of ARID1A in all types of cancer. Image was adopted from Cosmic website (https://cancer.sanger.ac.uk/cosmic), and double-checked in Cbioportal. (F) Interaction between ARID1A R1989* mutant and EZH2. HEK293T cells were transfected with WT Flag-ARID1A and R1989* mutant expressing plasmids, followed by EZH2 immunoprecipitation and immunoblotting with ARID1A and EZH2 antibodies. One of 3 is shown.