Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models
Shuanglian Wang, … , Mien-Chie Hung, Junwei Hou
Shuanglian Wang, … , Mien-Chie Hung, Junwei Hou
Published October 26, 2023
Citation Information: J Clin Invest. 2024;134(1):e166841. https://doi.org/10.1172/JCI166841.
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Research Article Oncology

Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models

Abstract

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.

Authors

Shuanglian Wang, Chiung-Wen Chang, Juan Huang, Shan Zeng, Xin Zhang, Mien-Chie Hung, Junwei Hou

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Figure 4

T cell–derived GZMB induces CCP by caspase-6 cleavage of GSDMC, and IFN-γ promotes GSDMC expression to enhance the killing effect of T cells and PARPi.

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T cell–derived GZMB induces CCP by caspase-6 cleavage of GSDMC, and IFN-...
(A) GZMB-mediated GSDMC cleavage by caspase-6 in MDA-MB-157 and Hs578t cells. Caspase-6i, caspase-6 inhibitor; caspase-8i, caspase-8 inhibitor. (B) MDA-MB-436 cells expressing WT GSDMC (GSDMC-WT) or the D365A mutant (GSDMC-mut) were treated with GZMB or inhibitors of caspase-6 or caspase-8. Immunoblotting of GSDMC cleavage. (C) Same as B, except that cells were cocultured with T cells instead of GZMB treatment. (D) Cell death measured by LDH release (LDH-released cell death) induced by GZMB in MDA-MB-157 and Hs578t cells (n = 3). (E) LDH-released cell death induced by cytotoxic T cells in MDA-MB-157 and Hs578t cells treated with caspase-6 siRNA (6si) and/or caspase-8 siRNA (8si) (n = 3). (F) LDH-released cell death induced by cytotoxic T cell in MDA-MB-436 cells with expression of vector, GSDMC-WT, and GSDMC-mut (n = 3). (G) Quantification of cytokine levels by ELISA in tumors of Figure 2F. (H) GSDMC induction by cytokines indicated in BT549 and HCC38 cells. (I) IFN-γ enhanced LDH-released cell death induced by olaparib at indicated concentration in BT549 and HCC38 cells (n = 3). (J and K) IFN-γ enhanced LDH-released cell death in BT549 and HCC38 cells treated with cytosolic delivery of GZMB (J) or cocultured with cytotoxic T cells (K) (n = 3). Data represent mean ± SD. 1-way ANOVA was used for D–F. 2-way ANOVA was used for I. Unpaired 2-tailed t test was used for G, J, and K. *P < 0.05, **P < 0.01, ***P < 0.001.