[초청강연] Application of inflammation and cell death in infectious diseases and cancer

Application of inflammation and cell death in infectious diseases

and cancer
Rajendra Karki

St. Jude Children’s Research Hospital, Memphis, TN, USA

Abstract
Cell death has been associated with pathologies observed in cytokine storm syndromes caused
by excessive production of pro-inflammatory cytokines and interferons during SARS-CoV-2
infection. Of the multiple inflammatory cytokines or interferons produced by innate immune cells
during the viral infection, combination of TNF and IFN-γ specifically induced cell death, which is
characterized by gasdermin–mediated pyroptosis, caspase-8–mediated apoptosis, and
MLKL–mediated necroptosis, collectively called PANoptosis. Mechanistically, the STAT1/IRF1
axis activated by TNF and IFN-γ co-treatment induced nitric oxide production to drive
PANoptosis. Neutralizing TNF and IFN-γ protected mice from lethality in various models of
cytokine storm syndromes. Furthermore, cell death dependent cytokine storm impedes the
efficacy of IFN therapy during coronavirus infection. Since resisting cell death is one of the
hallmarks of tumorigenesis, innate immunity and cell death can be exploited to treat cancer.
TNF and IFN-γ induced PANoptosis in several human cancer cell lines and inhibited the tumor
development in tumor transplant model. Moreover, IRF1 deficiency led to colorectal
tumorigenesis. In addition to TNF and IFN-γ, PANoptosis was induced by KPT-330, an FDA
approved drug for the treatment of refractory multiple myeloma, in the presence of IFNs. The
IFN inducible, ADAR1 suppressed KPT and IFN–induced PANoptosis by interacting with ZBP1.
Treating mice with KPT and IFN regressed melanoma in a ZBP1-dependent manner. Altogether,
innate immunity and cell death can be harnessed to treat cytokine storm associated diseases
and tumorigenesis.