The combination
therapy of
platinum-based
chemotherapy and
PD-L1 inhibitors but not the single anti-PD-L1
therapy has significantly improved the prognosis of patients with
small-cell lung cancer (SCLC). However, the synergistic mechanism of combination
therapy has not been fully elucidated. In this work, we identified a positive correlation between the expression of pyroptosis-related
proteins Gasdermin E (GSDME) and the survival rates of patients with SCLC. Importantly, it was shown that human SCLC cell lines with high expression of GSDME showed more sensitivity to
cisplatin, as well as
cisplatin plus anti-PD-L1 treatment both in vitro and in vivo. Mechanically,
cisplatin induced the activation of GSDME and the release of
cytokines including
IL-12, which enhance the expression of IFN-γ in T cells in the
tumor immune microenvironment (TME) and subsequently improve anti-PD-L1 response. Altogether, our work demonstrates that
cisplatin could induce GSDME-dependent cell pyroptosis to improve the response of anti-PD-L1
therapy though switching the TME from "cold" to "hot" in SCLC, indicating GSDME as a response
biomarker for combination
therapy of anti-PD-L1 and
chemotherapy, as well as a potential target to sensitize the response to
PD-L1 inhibitor therapy in future.