Year: 2020
Type: article
Abstract: Myc amplification may transcriptionally regulate immune inhibition-associated molecules such as CD47 and PD-L1 in a mouse model of T cell acute lymphoblastic leukemia (12).In addition, Kras G12D can cause an increase in expression of the inflammatory cytokine GM-CSF in a mouse model of pancreatic neoplasia (13).Loss of P53 function activates the JAK2-STAT3 signaling pathway and promotes pancreatic tumor growth (14), and mutant P53 prolongs NF-kB activation and increases colorectal tumor incidence in a mouse model (15).These studies reveal a general mechanistic connection between cancer driver mutation-related inflammation and cancer progression in different model systems.However, the link among cancer driver gene mutations, T cell immunity, and immunotherapy response has not been established in patients with cancer.Thus, we have attempted to explore whether cancer genetic driver mutation(s) are capable of directly driving cancer immune phenotype, contributing to IFN signature and T cell immunity, and affecting immunotherapy response in models and in patients with cancer.Given that the most recurrent cancer driver genetic mutations, including MYC, APC, TP53, and KRAS, have been examined, in this work we focused our studies on the cancer driver epigenetic mutations such as ARID1A mutations (16)(17)(18)(19).ARID1A belongs to the SWI/SNF complex and is a core member of the ATP-dependent polymorphic BRG/BRM-associated factor (BAF) chromatin remodeling unit.SWI/SNF complex mutations 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.
DOI: 10.1172/jci134402
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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G109073144, G1100779969, Novel immunosupressive macrophages in human ovarian tumor, G1404790370, Immune Impact on Cancer Chemoresistance, Memory T Cells in the Tumor Microenvironment, G2108208586, G2117675313, G2351744653, G2880120850, G3015188539, G3296503969, G353336575, G3711721818, G372229224, G378389786, Ovarian Cancer Epigenetics, Immunity and Therapy, G6132983747, G6612995435, G690399298, G7417736722, Naive T cells in Cancer Immune Evasion and Immunotherapy, G847526124, G9000030589, G9000031927, G9000073226, G9000148444, G9000265101, Cancer Center Support Grant, Michigan Prostate SPORE 2025-2030, Consolidated Basic Cancer Research Program
OpenAlex ID: W3004964052