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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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 5

ARID1A functionally interacts with EZH2.

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ARID1A functionally interacts with EZH2. (A and B) Effect of ARID1A on E...
(A and B) Effect of ARID1A on EZH2-mediated Th1-type chemokine repression in ovarian cancer cells. ARID1A WT or knockout OC8 cells were pretreated with GSK126, following IFN-γ treatment for 8 hours. CXCL9 (A) and CXCL10 (B) expression were quantified by real-time PCR. Mean ± SD, n = 3 with repeats, *P = 0.0032 (A), *P = 0.0014 (B), Student’s 2-tailed t tests. (C and D) Effect of ARID1A on H3K27me3-mediated Th1-type chemokine repression in ovarian cancer cells. ARID1A WT or knockout OC8 cells were treated with IFN-γ for 6 hours. H3K27me3 ChIP was performed. H3K27me3 levels on the promoters of CXCL9 and CXCL10 were normalized to the input. Mean ± SD, n = 3–4, *P = 0.00155 (C), *P = 0.00003 (D), Student’s 2-tailed t tests. (E) Effect of ARID1A C-terminal truncation on CXCL9 gene expression in ovarian cancer cells. ARID1A-knockout OVCA429 cells were transfected with full-length ARID1A, ARID1A mutant C, and ARID1A mutant D (ARID1A C-terminal truncation) (see Figure 4B). CXCL9 expression was quantified by real-time PCR. (n = 3, *P = 0.0017, Student’s 2-tailed t tests). (F) Effect of ARID1A R1989* mutation on CXCL10 gene expression in ovarian cancer cells. ARID1A-knockout OVCA429 cells were transfected with WT ARID1A or ARID1A R1989* mutants and stimulated with IFN-γ for 12 hours. CXCL10 expression was quantified by real-time PCR. (n = 3, *P = 0.028, Student’s t tests). (G) Venn diagram depicting overlap between genes significantly regulated following IFN-γ stimulation (blue), ARID1A knockout (red), or GSK126 treatment (yellow) in OVCA-429 cells. Stacked bar plot depicting the distribution of ARID1A– or GSK126– regulation status of IFN-γ–responsive genes. (H) Log2 fold change (LFC) of top IFN-γ–responsive genes that are significantly regulated following ARID1A knockout or GSK126 treatment, n = 2.