State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Adv Sci (Weinh). 2024 Nov;11(43):e2402244. doi: 10.1002/advs.202402244. Epub 2024 Sep 24.
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.
尽管免疫疗法在某些实体瘤方面取得了重大进展，但胰腺导管腺癌（PDAC）仍然对此类干预措施反应不佳，主要是由于其高度免疫抑制的肿瘤微环境（TME）中 CD8 T 细胞浸润有限。本研究探讨了表观遗传因子 Sin3B 在 PDAC TME 中的作用。使用小鼠 PDAC 模型，我们发现肿瘤细胞内在的 Sin3B 缺失重塑了 TME，增加了 CD8 T 细胞浸润和细胞毒性，从而阻碍了肿瘤的进展并增强了对抗 PD-1 治疗的敏感性。缺乏 Sin3B 的肿瘤细胞对干扰素-γ（IFNγ）表现出增强的 CXCL9/10 分泌，通过 CXCL9/10-CXCR3 轴形成正反馈回路，从而增强了针对 PDAC 的抗肿瘤免疫反应。从机制上讲，Sin3B 缺失揭示了广泛的表观遗传调控，特别是在 PDAC 细胞中与免疫反应相关的基因上增强了 H3K27Ac 分布。与小鼠模型的研究结果一致，对人类 PDAC 样本的分析表明，SIN3B 水平与 CD8 T 细胞浸润和 CXCL9/10 表达呈显著负相关。值得注意的是，SIN3B 表达水平较低的 PDAC 患者对抗 PD-1 治疗的反应更为有利。这些发现表明，靶向 SIN3B 可以增强细胞毒性 T 细胞浸润到肿瘤部位，并提高 PDAC 的免疫治疗效果，为该挑战性疾病提供了治疗生物标志物或靶标的潜在途径。
