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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

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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 3

GSDMC-mediated CCP increases the population and tumor infiltration of memory T cell.

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GSDMC-mediated CCP increases the population and tumor infiltration of me...
(A) 4TO7-Brca–KO cells stably expressing an empty vector (vector) or WT mouse Gsdmc (Gsdmc-WT) or the D263A mutant (Gsdmc-mut) were inoculated into the mammary fat pad of immunocompetent BALB/c mice (n = 10). Mice were administered olaparib. Percentage of tumor-infiltrating CD8+ T cells was analyzed. (B) Overexpression of eGFP in the stable cells as indicated in A. Then cells and mice were treated same as in A. Mean numbers of eGFP tetramer+ (eGFP tet+) CD8+ T cells per gram of tumor (left). Percentage of IFN-γ+ (middle) or TNF-α+ (right) CD8+ T cells activated by eGFP peptide. (C) Frequency of memory T cell subsets in lymph node (LN), spleen, and tumors of A. Tex, exhausted T cell. (D) Initial tumor challenge and mice treatment were same as in A. Tumors were removed on day 18. Then tumor rechallenge of 4TO7 parental cells was performed 60 days after tumor removal. Tumor growth was shown (n = 10). (E) Stable cells as indicated in A were inoculated into the mammary fat pad of immunocompetent BALB/c mice (n = 10). 4TO7 parental cells were simultaneously injected into contralateral mammary fat pad. Mice were administered olaparib. Tumor growth of 4TO7 parental cells was monitored. (F and G) 4TO7-Brca–KO Gsdmc-WT cells were inoculated into BALB/c mice (n = 10). Mice were administered olaparib. Depletion of CD8+ T cell with anti-CD8. Curves of tumor growth (F) and survival (G). (H) Growth curve of 4TO7-Gsdmc-WT and 4TO7-vector tumors in BALB/c mice (n = 10) treated with olaparib or PD-1 antibody or the combination. Data represent mean ± SD. 1-way ANOVA was used for A, B, D, E, and H. Unpaired 2-tailed t test was used for F. Log-rank test was used for G. **P < 0.01, ***P < 0.001.

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