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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
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.
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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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