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 1

ARID1A gene status correlates with cancer immune signature.

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ARID1A gene status correlates with cancer immune signature. (A–H) Relati...
(A–H) Relationship between ARID1A mutations and immune signature genes. RNA-Seq was conducted in patients with OCCC. Nine patients with ARID1A mutations, 9 patients with WT ARID1A. (A) Top 5 GSEA pathways of transcriptome between WT and mutated ARID1A cancers are shown. (B) Th1-type immune response GSEA pathway is enriched in WT ARID1A OCCC patients, Q = 0.025529487. (C) Cytotoxic gene signatures were enriched in WT ARID1A OCCC patients, Q = 0.007425. (D–H) CXCL9 (D), CXCL10 (E), CXCL11 (F), TCR (G), and CD8 (H) RPKM values of represented transcripts are shown. *P < 0.05. (I–L) ARID1A gene expression levels correlated with CXCL10 (I), CD8A (J), PRF1 (K), IRF1 (L) in 8 OCCC patients from Wu et al. study (30). (M–P) ARID1A gene expression levels correlated with CXCL9 (M), CXCL10 (N), CXCL11 (O), and IRF1 (P) gene expression levels in 47 WT ARID1A metastatic melanoma patients. (Q–T) CXCL9 (Q), CXCL10 (R), CXCL11 (S), CD8A (T) gene expression levels were higher in ARID1A high group, compared with ARID1A low group in TCGA pan-cancer (PANCAN) data set: 3838 patients in ARID1A high group, 3839 patients in ARID1A low group. For box-and-whisker plots in Q–T, the center line denotes the median value (50th percentile); the box contains the 25th to 75th percentiles of the data set. The whiskers mark the maximum and minimum values, *P < 0.001.