CTLA-4 blockade induces tumor pyroptosis via CD8+T cells in head and neck squamous cell carcinoma

Immune checkpoint blockade (ICB) treatment has demon-strated excellent medical effects in oncology, and it is one of the most sought after immunotherapies for tumors. However, there are several issues with ICB therapy, including low response rates and a lack of effective efficacy predictors. Gasder-min-mediated pyroptosis is a typical inflammatory death mode. We discovered that increased expression of gasdermin protein was linked to a favorable tumor immune microenvironment and prognosis in head and neck squamous cell carcinoma (HNSCC). We used the mouse HNSCC cell lines 4MOSC1 (responsive to CTLA-4 blockade) and 4MOSC2 (resistant to CTLA-4 blockade) orthotopic models and demonstrated that CTLA-4 blockade treatment induced gasdermin-mediated py-roptosis of tumor cells, and gasdermin expression positively correlated to the effectiveness of CTLA-4 blockade treatment. We found that CTLA-4 blockade activated CD8+ T cells and increased the levels of interferon g (IFN-g) and tumor necrosis factor a (TNF-a) cytokines in the tumor microenvironment. These cytokines synergistically activated the STAT1/IRF1 axis to trigger tumor cell pyroptosis and the release of large amounts of inflammatory substances and chemokines. Collectively, our findings revealed that CTLA-4 blockade triggered tumor cells pyroptosis via the release of IFN-g and TNF-a from activated CD8+ T cells, providing a new perspective of ICB.

Automated summary

Immune checkpoint blockade (ICB) treatment is effective in oncology, but has limitations including low response rates and a lack of efficacy predictors. Gasdermin protein expression is associated with a favorable tumor immune microenvironment and prognosis in head and neck squamous cell carcinoma. CTLA-4 blockade treatment induces gasdermin-mediated pyroptosis of tumor cells, with gasdermin expression correlating with treatment effectiveness. CTLA-4 blockade activates CD8+ T cells and increases levels of IFN-g and TNF-a cytokines, triggering tumor cell pyroptosis and release of inflammatory substances and chemokines.