Modulation of cytokine storm and tumorigenesis by innate immunity

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. 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, a 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.

Biography

Currently, I am working as a Lab Director at the Department of Immunology in St. Jude Children’s Research Hospital, Tennessee, USA. I completed my Bachelor in Pharmaceutical Sciences from Pokhara University, Nepal; and my Master and PhD in Biological Sciences from Mokpo National University, South Korea. I studied the role of oriental herbs and their active constituents in the prevention of diseases associated with metabolic syndrome such as atherosclerosis, diabetes and obesity during my Master and PhD. I did a short Post-Doctoral Training at the Department of Phamacology and Toxicology in University of Missouri-Kansas City, where I studied pro-oxidant sensing ability of Toll-like Receptors. Recognizing my productivity and my interests in innate immunity, I got opportunity to continue my Post-Doctoral Training at the Department of Immunology, St. Jude Children’s Research Hospital, where I primarily focused on role of innate immunity in pathogenesis of several diseases like infectious, autoinflammatory, and autoimmune diseases and cancer. In total, I contributed to 71 publications, among which 29 are as the first author, 3 are as the corresponding author, 1 is a Book Chapter and 2 are Patents. Additionally, a first authored manuscript is in press. Furthermore, I am one of the top 2% of highly cited scientists in the field of immunology as reported by a new study published in PloS Biology by scientists from Standford University.

Pattern-recognition receptors are germ-line encoded innate immune sensors which detect pathogens and danger signals. These receptors activate signaling pathways and mediate the production of inflammatory cytokines, type I interferons, and other anti-microbial molecules. I use cutting-edge technology to study the mechanisms by which host sensors recognize bacteria, viruses, fungi, and parasites, and how these sensors shape the overall immune response to infection (Cell Host and Microbe 2015; Cell 2016, Cell 2018, Cell 2021). I also study the molecular basis by which uncontrolled inflammation can lead to the development of cancer, autoimmunity, and inflammatory diseases (Nature 2016, Cell 2021, Cell Reports 2021).

Recognizing my contributions in innate immunity, I was invited to write a Book Chapter on Pattern Recognition Receptors and the IL-1 family in William Paul’s Fundamental Immunology, 8^th ed William E. Paul, which is currently in Press. During the crisis brought by SARS-CoV-2 infection, I highlighted the pathogenic role of two cytokines, TNF and IFN-γ (Cell, 2021) in inducing and perpetuating cytokine storm. I was able to show that neutralizing antibodies against TNF and IFN-γ would provide protection against SARS-CoV-2 infection and other cytokine storm associated diseases like HLH and endotoxic shock. These applications of neutralizing antibodies for TNF and IFN-γ have recently been well documented in an international patent (WO2022061266). Moreover, cell death inducing ability of certain compounds can be harnessed to treat cancer. Based on this concept, I showed that combining IFN with KPT-330, an FDA approved drug could inhibit cancer growth and the study also clarified the reasons behind the failure of IFN therapy in cancer treatment (Cell Reports, 2021). The application of IFN and KPT-330 for cancer treatment has been submitted for a patent (USA, Serial No. 63/196, 986). One of my recent findings, which is in press now  (Science Immunology, 2022), demonstrates the ways to improve the efficacy of IFN therapy during SARS-CoV-2 infection.

I was a recipient of the Milstein Travel Award (2018) from International Cytokine and Interferon Society, Thermo Fisher Trainee Achievement Award (2017), and Travel awards (2017, 2015) from the American Association of Immunologists.

I am extremely excited to share with you my passion and vision for scientific research, specifically in multidisciplinary approaches to promote the application of innate immunity in cell/tissue biology, health and disease, and drug discovery. As my expertise in innate immunity spans numerous facets of translational research–heavily focused on experimentation frameworks– I will facilitate a collaborative environment that inspires cutting-edge research opportunities for students, colleagues, and collaborators. In addition to research pursuits, I am an experienced educator and dedicated mentor.