Killer cell-triggered pyroptosis in tumor cells
Killer cell-mediated tumor cell killing is a key, final step of anti-tumor immune protection. CD8 cytotoxic T cells and Natural Killer (NK) cells use the cytotoxic proteases granzymes (Gzms) to eliminate tumor cells. Gzms, delivered by the pore-forming protein perforin (PFN), cleave a number of substrates in target cells to induce cell death. Like apoptosis, killer cell-mediated target cell death has always been thought of as noninflammatory. However, recent studies suggest an emerging role of the inflammatory cell death, called pyroptosis, in killer cell-mediated tumor elimination. Pyroptosis is a gasdermin-mediated programmed necrotic cell death that activates immune responses.
Gasdermin (GSDM) family proteins, which include GSDM A-E, trigger pyroptosis after their N-terminal (NT) domains are cleaved by proteases from their C-terminal inhibitory domains and form pores on the plasma membrane. Inflammatory caspase-1/4/5/11 cleave and activate GSDMD while apoptotic caspase-3 processes and activates GSDME. Our recent study shows that killer cell GzmB activates pyroptosis in GSDME-expressing target cells by both directly cleaving GSDME and indirectly activating caspase-3. The resulting pyroptosis further increases the number and functions of tumor infiltrating CD8 T cells and NK cells, thus enhancing killer cell-mediated anti-tumor immunity and leading to tumor suppression. This study revealed a critical role of pyroptosis in enhancing anti-tumor immunity.
Our lab is further exploring the roles of pyroptosis in tumor immunology. We aim to understand the mechanism underlying how pyroptosis activates anti-tumor immunity; investigate how killer cell-triggered pyroptosis is regulated; and develop pyroptosis-based therapeutic interventions to enhance anti-tumor immunity.