PARP inhibitors enhance antitumor immune responses by triggering pyroptosis via TNF–caspase 8–GSDMD/E axis in ovarian cancer

作者：Yu Xia, Pu Huang, Yiyu Qian, Zanhong Wang, Ning Jin, Xin Li, Wen Pan, Siyuan Wang, Ping Jin, Emmanuel Kwateng Drokow, Li Xiong, Qi Zhang, Zhengmao Zhang, Pingfei Li, Yong Fang, Xiang‐Ping Yang, Zhiqiang Han, Qinglei Gao · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2024 · DOI：10.1136/jitc-2024-009032 · 被引用次数：40 · 研究领域：Inflammasome and immune disorders、PARP inhibition in cancer therapy、Cancer Immunotherapy and Biomarkers

Background In addition to their established action of synthetic lethality in tumor cells, poly(ADP-ribose) polymerase inhibitors (PARPis) also orchestrate tumor immune microenvironment (TIME) that contributes to suppressing tumor growth. However, it remains not fully understood whether and how PARPis trigger tumor-targeting immune responses. Methods To decode the immune responses reshaped by PARPis, we conducted T-cell receptor (TCR) sequencing and immunohistochemical (IHC) analyses of paired clinical specimens before and after niraparib monotherapy obtained from a prospective study, as well as ID8 mouse ovarian tumors. To validate the induction of immunogenic cell death (ICD) by PARPis, we performed immunofluorescence/IHC staining with homologous recombination deficiency tumor cells and patient-derived xenograft tumor tissues, respectively. To substantiate that PARPis elicited tumor cell pyroptosis, we undertook comprehensive assessments of the cellular morphological features, cleavage of gasdermin (GSDM) proteins, and activation of TNF-caspase signaling pathways through genetic downregulation/depletion and selective inhibition. We also evaluated the critical role of pyroptosis in tumor suppression and immune activation following niraparib treatment using a syngeneic mouse model with implanting CRISPR/Cas9 edited Gsdme −/ − ID8 tumor cells into C57BL/6 mice. Results Our findings revealed that PARPis augmented the proportion of neoantigen-recognized TCR clones and TCR clonal ...