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

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, includin...

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Autores principales: Chen, Xin‐Yu, Li, Bin, Wang, Ye, Jin, Juan, Yang, Yu, Huang, Lei‐Huan, Yang, Meng‐Di, Zhang, Jian, Wang, Bi‐Yun, Shao, Zhi‐Ming, Ni, Ting, Huang, Sheng‐Lin, Hu, Xi‐Chun, Tao, Zhong‐Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10508140/
https://www.ncbi.nlm.nih.gov/pubmed/37434394
http://dx.doi.org/10.1002/cac2.12465
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author Chen, Xin‐Yu
Li, Bin
Wang, Ye
Jin, Juan
Yang, Yu
Huang, Lei‐Huan
Yang, Meng‐Di
Zhang, Jian
Wang, Bi‐Yun
Shao, Zhi‐Ming
Ni, Ting
Huang, Sheng‐Lin
Hu, Xi‐Chun
Tao, Zhong‐Hua
author_facet Chen, Xin‐Yu
Li, Bin
Wang, Ye
Jin, Juan
Yang, Yu
Huang, Lei‐Huan
Yang, Meng‐Di
Zhang, Jian
Wang, Bi‐Yun
Shao, Zhi‐Ming
Ni, Ting
Huang, Sheng‐Lin
Hu, Xi‐Chun
Tao, Zhong‐Hua
author_sort Chen, Xin‐Yu
collection PubMed
description 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.
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spelling pubmed-105081402023-09-20 Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors Chen, Xin‐Yu Li, Bin Wang, Ye Jin, Juan Yang, Yu Huang, Lei‐Huan Yang, Meng‐Di Zhang, Jian Wang, Bi‐Yun Shao, Zhi‐Ming Ni, Ting Huang, Sheng‐Lin Hu, Xi‐Chun Tao, Zhong‐Hua Cancer Commun (Lond) Original Articles 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. John Wiley and Sons Inc. 2023-07-11 /pmc/articles/PMC10508140/ /pubmed/37434394 http://dx.doi.org/10.1002/cac2.12465 Text en © 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Chen, Xin‐Yu
Li, Bin
Wang, Ye
Jin, Juan
Yang, Yu
Huang, Lei‐Huan
Yang, Meng‐Di
Zhang, Jian
Wang, Bi‐Yun
Shao, Zhi‐Ming
Ni, Ting
Huang, Sheng‐Lin
Hu, Xi‐Chun
Tao, Zhong‐Hua
Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors
title Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors
title_full Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors
title_fullStr Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors
title_full_unstemmed Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors
title_short Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors
title_sort low level of arid1a contributes to adaptive immune resistance and sensitizes triple‐negative breast cancer to immune checkpoint inhibitors
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10508140/
https://www.ncbi.nlm.nih.gov/pubmed/37434394
http://dx.doi.org/10.1002/cac2.12465
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