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.
View: Text | PDF
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

×

Figure 3

ARID1A regulates IFN-γ–signaling gene chromatin accessibility.

Options: View larger image (or click on image) Download as PowerPoint
ARID1A regulates IFN-γ–signaling gene chromatin accessibility. (A and B)...
(A and B) Genome-wide analysis (A) and Venn diagram (B) showing differentially accessible chromatin sites (|LFC| > 0.5) after IFN-γ stimulation in ARID1A-proficient (WT) and ARID1A-deficient (KO) OVCA-429 cells. (C) Chromatin accessibility heatmaps of ARID1A-proficient (WT) and ARID1A-deficient (KO) OVCA-429 cells. The heatmaps demonstrated the chromatin sites in cluster I (top) and cluster III (bottom). Aggregated peak intensity within 1 kb center of chromatin regions with differential accessibility is shown. (D) IRF2-binding motif was among the most significantly enriched motifs in clusters I, II, and III. (E) Examples of IFN-γ–responsive sites with less accessibilities in ARID1A-deficient (KO) OVCA-429 cells. The graph shows accessible sites near CXCL9, CXCL10, and CXCL11. (F) Pie chart illustrating accessibility changes of chromosomal sites adjacent to promoters (within 5 kb) of IFN-γ–responsive and ARID1A-affected genes. Blue: Promoters with differentially accessible sites following ARID1A loss. Yellow: Promoters without significant changed sites following ARID1A loss. (G and H) Correlation between ARID1A expression and average chromatin accessibility peaks near CXCL9 gene (221 peaks) (G) and CXCL10 (H) (219 peaks). Each dot represents an individual donor. ARID1A gene expression is log transformed. Eleven patients with WT skin cutaneous melanoma. P = 0.0464 (G), P = 0.0151 (H).