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SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production
Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We foun...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378164/ https://www.ncbi.nlm.nih.gov/pubmed/37279067 http://dx.doi.org/10.1172/JCI163841 |
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author | Chen, Liyun Shi, Victoria Wang, Songyan Sun, Lulu Freeman, Rebecca Yang, Jasmine Inkman, Matthew J. Ghosh, Subhajit Ruiz, Fiona Jayachandran, Kay Huang, Yi Luo, Jingqin Zhang, Jin Cosper, Pippa Luke, Clifford J. Spina, Catherine S. Grigsby, Perry W. Schwarz, Julie K. Markovina, Stephanie |
author_facet | Chen, Liyun Shi, Victoria Wang, Songyan Sun, Lulu Freeman, Rebecca Yang, Jasmine Inkman, Matthew J. Ghosh, Subhajit Ruiz, Fiona Jayachandran, Kay Huang, Yi Luo, Jingqin Zhang, Jin Cosper, Pippa Luke, Clifford J. Spina, Catherine S. Grigsby, Perry W. Schwarz, Julie K. Markovina, Stephanie |
author_sort | Chen, Liyun |
collection | PubMed |
description | Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased MDSC and tumor-associated macrophage (TAM) infiltration, contributing to T cell inhibition, and this was further augmented upon radiation. Intratumoral knockdown (KD) of Serpinb3a resulted in tumor growth inhibition and reduced CXCL1 and S100A8/A expression and MDSC and M2 macrophage infiltration. These changes led to enhanced cytotoxic T cell function and sensitized tumors to radiotherapy (RT). We further revealed that SERPINB3 promoted STAT-dependent expression of chemokines, whereby inhibition of STAT activation by ruxolitinib or siRNA abrogated CXCL1/8 and S100A8/ A9 expression in SERPINB3 cells. Patients with elevated pretreatment SCCA levels and high phosphorylated STAT3 (p-STAT3) had increased intratumoral CD11b(+) myeloid cells compared with patients with low SCCA levels and p-STAT3, who had improved overall survival after RT. These findings provide a preclinical rationale for targeting SERPINB3 in tumors to counteract immunosuppression and improve the response to RT. |
format | Online Article Text |
id | pubmed-10378164 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-103781642023-08-01 SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production Chen, Liyun Shi, Victoria Wang, Songyan Sun, Lulu Freeman, Rebecca Yang, Jasmine Inkman, Matthew J. Ghosh, Subhajit Ruiz, Fiona Jayachandran, Kay Huang, Yi Luo, Jingqin Zhang, Jin Cosper, Pippa Luke, Clifford J. Spina, Catherine S. Grigsby, Perry W. Schwarz, Julie K. Markovina, Stephanie J Clin Invest Research Article Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased MDSC and tumor-associated macrophage (TAM) infiltration, contributing to T cell inhibition, and this was further augmented upon radiation. Intratumoral knockdown (KD) of Serpinb3a resulted in tumor growth inhibition and reduced CXCL1 and S100A8/A expression and MDSC and M2 macrophage infiltration. These changes led to enhanced cytotoxic T cell function and sensitized tumors to radiotherapy (RT). We further revealed that SERPINB3 promoted STAT-dependent expression of chemokines, whereby inhibition of STAT activation by ruxolitinib or siRNA abrogated CXCL1/8 and S100A8/ A9 expression in SERPINB3 cells. Patients with elevated pretreatment SCCA levels and high phosphorylated STAT3 (p-STAT3) had increased intratumoral CD11b(+) myeloid cells compared with patients with low SCCA levels and p-STAT3, who had improved overall survival after RT. These findings provide a preclinical rationale for targeting SERPINB3 in tumors to counteract immunosuppression and improve the response to RT. American Society for Clinical Investigation 2023-08-01 /pmc/articles/PMC10378164/ /pubmed/37279067 http://dx.doi.org/10.1172/JCI163841 Text en © 2023 Chen et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Chen, Liyun Shi, Victoria Wang, Songyan Sun, Lulu Freeman, Rebecca Yang, Jasmine Inkman, Matthew J. Ghosh, Subhajit Ruiz, Fiona Jayachandran, Kay Huang, Yi Luo, Jingqin Zhang, Jin Cosper, Pippa Luke, Clifford J. Spina, Catherine S. Grigsby, Perry W. Schwarz, Julie K. Markovina, Stephanie SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production |
title | SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production |
title_full | SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production |
title_fullStr | SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production |
title_full_unstemmed | SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production |
title_short | SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production |
title_sort | scca1/serpinb3 suppresses antitumor immunity and blunts therapy-induced t cell responses via stat-dependent chemokine production |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378164/ https://www.ncbi.nlm.nih.gov/pubmed/37279067 http://dx.doi.org/10.1172/JCI163841 |
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