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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

The Journal of clinical investigation, 2023-08, Vol.133 (15) [Periódico revisado por pares]

American Society for Clinical Investigation

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  • Título:
    SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production
  • Autor: 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
  • Assuntos: Cancer ; Care and treatment ; Chemokines ; Genetic aspects ; Health aspects ; Immune response ; Oncology ; Patient outcomes ; Protease inhibitors ; Radiotherapy
  • É parte de: The Journal of clinical investigation, 2023-08, Vol.133 (15)
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: 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.sup.+] 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.
  • Editor: American Society for Clinical Investigation
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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