Seminar of Dr. Feng Shao

We are honored to host Dr. Feng Shao, investigator and deputy director at National Institute of Biological Sciences (NIBS, Beijing, China) for a seminar. Feng is a fantastic researcher working at the interface between bacterial pathogen and host inflammation. He will tell us about his work linking antitumor immunity, pyroptotic cell death and Cancer.

Activation of antitumor immunity by bacteria-derived signals: Pyroptosis & Beyond

Abstract: 

Pyroptosis is a proinflammatory cell death executed by the gasdermin-family pore-forming proteins. Among the family, gasdermin D (GSDMD) is cleaved by inflammasome-activated caspase-1 and LPS-activated caspase-11/4/5. The cleavage unmasks the pore-forming domain in GSDMD that perforates plasma membrane. Using a bioorthogonal chemical biology approach allowing controlled delivery of active gasdermin into tumors in mice, we found that pyroptosis of < 15% tumour cells could clear the entire 4T1 mammary tumor graft, which was absent in immune-deficient mice or upon T-cell depletion. Thus, pyroptosis stimulates potent and effective antitumour immunity. In antitumor immunity, cytotoxic lymphocyte relies on granzymes to kill target cells. We found that natural killer cells and cytotoxic T lymphocytes kill GSDMB-positive cells through pyroptosis, mediated by granzyme A (GZMA) cleavage of GSDMB. IFN-g upregulates GSDMB expression and promotes pyroptosis of cancer cells including that by CAR-T/TCR-T cells. Thus, gasdermin-executed pyroptosis serves as a cytotoxic lymphocyte killing mechanism, playing an important role in cancer immunotherapy. We recently discovered a novel cytosolic innate immune receptor alpha-kinase 1 (ALPK1) that recognizes a bacterial metabolite ADP-heptose. ADP-heptose-activated ALPK1 phosphorylates the TIFA adaptor, thereby stimulating the NF-kB signaling and proinflammatory cytokine production. I will also discuss the function of ALPK1-TIFA axis in cancer immunity.

Representative publications:

1. Zhong X, Zeng H, Zhou Z, Su Y, Cheng H, Hou Y, She Y, Feng N, Wang J, Shao F#, and Ding J# (2023) Structural mechanisms for regulation of GSDMB pore-forming activity. Nature, 616, 598-605.(#corresponding authors)
2. Li Z, Liu W, Fu J, Cheng S, Xu Y, Wang Z, Liu X, Shi X, Liu Y, Qi X, Liu X#, Ding J, Shao F# (2021) Shigella evades intracellular LPS-induced pyroptosis by arginine ADP-riboxanation of caspase-11. Nature, 599, 290-295.
3. Zhou Z, He H, Wang K, Shi X, Wang Y, Su Y, Wang Y, Li D, Liu W, Zhang Y, Shen L, Han W, Shen L, Ding J, Shao F# (2020). Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science, 368(6494):eaaz7548.
4. Wang Q, Wang Y, Ding J, Wang C, Zhou X, Gao W, Huang H, Shao F# & Liu Z# (2020) A bioorthogonal system reveals antitumour immune function of pyroptosis, Nature, 579, 421-426.
5. Wang K, Sun Q, Zhong X, Zeng M, Zeng H, Shi X, Li Z, Wang Y, Zhao Q, Shao F# and Ding J# (2020) Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis, Cell, 180, 941-955.