Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple-negative breast cancer to immune checkpoint inhibitors
Xin-Yu Chen
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorBin Li
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorYe Wang
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorJuan Jin
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorYu Yang
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
Search for more papers by this authorLei-Huan Huang
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
Search for more papers by this authorMeng-Di Yang
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorJian Zhang
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorBi-Yun Wang
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorZhi-Ming Shao
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Search for more papers by this authorTing Ni
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
Search for more papers by this authorSheng-Lin Huang
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
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
Search for more papers by this authorCorresponding Author
Xi-Chun Hu
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Correspondence
Zhong-Hua Tao and Xi-Chun Hu, Department of Breast Cancer and Urologic Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Zhong-Hua Tao
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Correspondence
Zhong-Hua Tao and Xi-Chun Hu, Department of Breast Cancer and Urologic Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China.
Email: [email protected] and [email protected]
Search for more papers by this authorXin-Yu Chen
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorBin Li
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorYe Wang
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorJuan Jin
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorYu Yang
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
Search for more papers by this authorLei-Huan Huang
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
Search for more papers by this authorMeng-Di Yang
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorJian Zhang
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorBi-Yun Wang
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Search for more papers by this authorZhi-Ming Shao
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Search for more papers by this authorTing Ni
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
Search for more papers by this authorSheng-Lin Huang
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
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
Search for more papers by this authorCorresponding Author
Xi-Chun Hu
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Correspondence
Zhong-Hua Tao and Xi-Chun Hu, Department of Breast Cancer and Urologic Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Zhong-Hua Tao
Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
Correspondence
Zhong-Hua Tao and Xi-Chun Hu, Department of Breast Cancer and Urologic Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China.
Email: [email protected] and [email protected]
Search for more papers by this authorXin-Yu Chen and Bin Li contributed equally to this work.
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 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 via the ARID1A/NPM1/PD-L1 axis, leading to poor outcome but sensitivity to ICI treatment.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
RNA-seq, ChIP-seq and ATAC-seq data have been deposited to the GEO repository with the accession number GSE234179. Other datasets generated or analyzed during the current study are available in TCGA Program (https://www.cbioportal.org), UCSC Genome Browser (https://genome.ucsc.edu), GEO repository (https://www.ncbi.nlm.nih.gov/geo/), Molecular Signature Database (https://www.gsea-msigdb.org/gsea/msigdb/index.jsp), Gene Ontology Resource (http://geneontology.org), EnhancerDB (http://lcbb.swjtu.edu.cn/EnhancerDB/) and PubMed (https://pubmed.ncbi.nlm.nih.gov).
Supporting Information
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| cac212465-sup-0001-tableS1-S6.xlsx28.4 KB | Supporting information |
| cac212465-sup-0002-figureS1-S9.docx12.9 MB | Supporting information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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