Department of Otolaryngology Head and Neck Surgery.
Xiangya Cancer Center, and.
J Clin Invest. 2024 Jan 2;134(1):e166841. doi: 10.1172/JCI166841.
Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in the clinic due to an incomplete understanding on the molecular basis of PARPi function and a lack of good markers, beyond BRCA mutations, to predict response. Here, we show that gasdermin C (GSDMC) sensitized tumor cells to PARPi in vitro and in immunocompetent mice and caused durable tumor regression in an immune-dependent manner. A high expression level of GSDMC predicted better response to PARPi treatment in patients with triple-negative breast cancer (TNBC). PARPi treatment triggered GSDMC/caspase-8-mediated cancer cell pyroptosis (CCP) that enhanced PARPi killing of tumor cells. GSDMC-mediated CCP increased memory CD8+ T cell population in lymph node (LN), spleen, and tumor and, thus, promoted cytotoxic CD8+ T cell infiltration in the tumor microenvironment. T cell-derived granzyme B (GZMB) activated caspase-6, which subsequently cleaved GSDMC to induce pyroptosis. Interestingly, IFN-γ induced GSDMC expression, which, in turn, enhanced the cytotoxicity of PARPi and T cells. Importantly, GSDMC promoted tumor clearance independent of BRCA deficiency in multiple cancer types with PARPi treatment. This study identifies a general marker and target for PARPi therapy and offers insights into the mechanism of PARPi function.
几种聚 ADP-核糖聚合酶（PARP）抑制剂（PARPi）已被 FDA 批准用于治疗带有 BRCA 突变的癌症。BRCA 突变被认为通过诱导细胞凋亡来增强 PARPi 的杀伤作用。然而，由于对 PARPi 功能的分子基础缺乏完整的理解，以及缺乏除 BRCA 突变之外预测反应的良好标志物，临床上经常观察到对 PARPi 的耐药性。在这里，我们表明，Gasdermin C（GSDMC）在体外和免疫功能正常的小鼠中使肿瘤细胞对 PARPi 敏感，并以免疫依赖的方式导致持久的肿瘤消退。GSDMC 的高表达水平预测三阴性乳腺癌（TNBC）患者对 PARPi 治疗的反应更好。PARPi 治疗触发 GSDMC/caspase-8 介导的癌细胞细胞焦亡（CCP），增强了 PARPi 对肿瘤细胞的杀伤作用。GSDMC 介导的 CCP 增加了淋巴结（LN）、脾脏和肿瘤中记忆性 CD8+T 细胞群体，从而促进了肿瘤微环境中细胞毒性 CD8+T 细胞的浸润。T 细胞衍生的颗粒酶 B（GZMB）激活了 caspase-6，随后裂解 GSDMC 诱导细胞焦亡。有趣的是，IFN-γ 诱导了 GSDMC 的表达，进而增强了 PARPi 和 T 细胞的细胞毒性。重要的是，GSDMC 促进了肿瘤清除，而与多种癌症类型中 PARPi 治疗的 BRCA 缺乏无关。这项研究确定了 PARPi 治疗的一般标志物和靶标，并为 PARPi 功能的机制提供了深入的了解。
