Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors

作者：Xin‐Yu Chen, Bin Li, Ye Wang, Juan Jin, Yu Yang, Leihuan Huang, Meng‐Di Yang, Jian Zhang, Biyun Wang, Zhi‐Ming Shao, Ting Ni, Shenglin Huang, Xichun Hu, Zhonghua Tao · 发表于：癌症：英文版 · 年份：2023 · DOI：10.1002/cac2.12465 · 被引用次数：25 · 研究领域：Chromatin Remodeling and Cancer、Cancer Immunotherapy and Biomarkers、Peptidase Inhibition and Analysis

Abstract Background Immune checkpoint inhibitors (ICIs) shed new light on triple‐negative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens. Methods Databases, including The Cancer Genome Atlas, Gene Ontology Resource, University of California Santa Cruz Genome Browser, and Pubmed, were used to screen epigenetic modulators, regulators for CD8 + T cells, and transcriptional regulators of programmed cell death‐ligand 1 ( PD‐L1 ). Human peripheral blood mononuclear cell (Hu‐PBMC) reconstruction mice were adopted for xenograft transplantation. Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed. RNA‐sequencing, Western blotting, qPCR and immunohistochemistry were used to assess gene expression. Coculture assays were performed to evaluate the regulation of TNBC cells on T cells. Chromatin immunoprecipitation and transposase‐accessible chromatin sequencing were used to determine chromatin‐binding and accessibility. Results The epigenetic modulator AT‐rich interaction domain 1A ( ARID1A ) gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients. Low ARID1A expression in TNBC, causing an immunosuppressive microenvironment, promoted AIR and inhibited CD8 + T cell infiltration and activity through upregulating PD‐L1. However, ARID1A did not ...