1. SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer
- Author
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Zhengyan Zhang, Yingying Tang, Yu Wang, Junyi Xu, Xiaotong Yang, Mingzhu Liu, Massimiliano Mazzone, Ningning Niu, Yongwei Sun, Yujie Tang, and Jing Xue
- Subjects
anti‐PD1 treatment ,CD8+ T cell infiltration ,CXCL9/10‐CXCR3 axis ,pancreatic ductal adenocarcinoma ,tumor microenvironment ,Sin3B ,Science - Abstract
Abstract Despite progress significant advances in immunotherapy for some solid tumors, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive poorly responsive to such interventions, largely due to its highly immunosuppressive tumor microenvironment (TME) with limited CD8+ T cell infiltration. This study explores the role of the epigenetic factor Sin3B in the PDAC TME. Using murine PDAC models, we found that tumor cell‐intrinsic Sin3B loss reshapes the TME, increasing CD8+ T cell infiltration and cytotoxicity, thus impeding tumor progression and enhancing sensitivity to anti‐PD1 treatment. Sin3B‐deficient tumor cells exhibited amplified CXCL9/10 secretion in response to Interferon‐gamma (IFNγ), creating a positive feedback loop via the CXCL9/10‐CXCR3 axis, thereby intensifying the anti‐tumor immune response against PDAC. Mechanistically, extensive epigenetic regulation is uncovered by Sin3B loss, particularly enhanced H3K27Ac distribution on genes related to immune responses in PDAC cells. Consistent with the murine model findings, analysis of human PDAC samples revealed a significant inverse correlation between SIN3B levels and both CD8+ T cell infiltration and CXCL9/10 expression. Notebly, PDAC patients with lower SIN3B expression showed a more favorable response to anti‐PD1 therapy. The findings suggest that targeting SIN3B can enhance cytotoxic T cell infiltration into the tumor site and improve immunotherapy efficacy in PDAC, offering potential avenues for therapeutic biomarker or target in this challenging disease.
- Published
- 2024
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