{"doi":"10.1172/jci163841","title":"SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production","abstract":"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.","journal":"Journal of Clinical Investigation","year":2023,"id":323989,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":876229,"name":"Victoria Shi","orcid":"0000-0002-5235-2425","position":1,"is_corresponding":false},{"id":875403,"name":"Songyan Wang","orcid":"0000-0002-2926-382X","position":2,"is_corresponding":false},{"id":1025596,"name":"Lulu Sun","orcid":"0000-0001-7543-1532","position":3,"is_corresponding":false},{"id":792921,"name":"Rebecca Freeman","orcid":"0000-0002-2116-3648","position":4,"is_corresponding":false},{"id":1039887,"name":"Jasmine Yang","orcid":null,"position":5,"is_corresponding":false},{"id":447965,"name":"Matthew Inkman","orcid":"0000-0001-5490-2374","position":6,"is_corresponding":false},{"id":342512,"name":"Subhajit Ghosh","orcid":"0000-0002-5479-493X","position":7,"is_corresponding":false},{"id":357054,"name":"Fiona Ruiz","orcid":"0000-0003-3807-4980","position":8,"is_corresponding":false},{"id":357050,"name":"Kay Jayachandran","orcid":"0000-0003-3160-4299","position":9,"is_corresponding":false},{"id":357058,"name":"Yi Huang","orcid":"0000-0002-2867-1477","position":10,"is_corresponding":false},{"id":2218,"name":"Jingqin Luo","orcid":"0000-0003-2759-3072","position":11,"is_corresponding":false},{"id":31913,"name":"Jin Zhang","orcid":"0000-0002-9117-2793","position":12,"is_corresponding":false},{"id":509613,"name":"Pippa F. 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