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 Lei-Huan Huang Meng-Di Yang Jian Zhang Bi-Yun Wang Zhi-Ming Shao Ting Ni Sheng-Lin Huang Xi-Chun Hu Zhong-Hua Tao 

机构地区：[1]Department of Breast and Urologic Medical Oncology,Fudan University Shanghai Cancer Center,Shanghai,P. R. China [2]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai,P. R. China [3]State Key Laboratory of Genetic Engineering,Collaborative Innovation Center of Genetics and Development,Human Phenome Institute,School of Life Sciences,Fudan University,Shanghai,P. R. China [4]Key Laboratory of Breast Cancer in Shanghai,Department of Breast Surgery,Fudan University Shanghai Cancer Center,Shanghai,P. R. China [5]Precision Cancer Medicine Center,Fudan University Shanghai Cancer Center,Shanghai,P. R. China [6]Shanghai Key Laboratory of Medical Epigenetics,International Co-laboratory of Medical Epigenetics and Metabolism,Institutes of Biomedical Sciences,Shanghai Medical College,Fudan University,Shanghai,P. R. China

出　　处：《Cancer Communications》2023年第9期1003-1026,共24页癌症通讯（英文）

基　　金：National Science and Technology Major Project.Grant Number:2020ZX09201-013。

摘　　要：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 directly regulate PD-L1 expression.We found that ARID1A directly bound the promoter of nucleophosmin 1(NPM1)and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression,further activating PD-L1 transcription.In Hu-PBMC mice,atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity.In CTR20191353,ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients.Conclusions In AIR epigenetics,low ARID1A expression in TNBC contributed to AIR

关 键 词：adaptive immune resistance ARID1A CD8+T cell PD-L1 triple-negative breast cancer 

分 类 号：R73[医药卫生—肿瘤]