Metabolic and Pharmacological Modulations During IFN-γ signaling

Abstract

Interferons, initially discovered for their antiviral properties, play pivotal roles in various biological processes, including host defense against pathogens, tumor surveillance, and disease pathogenesis. Interferon-gamma (IFN-γ), a type II interferon primarily produced by T cells and natural killer cells, orchestrates diverse cellular responses through its canonical JAK-STAT signaling pathway, leading to the expression of numerous genes involved in immunity and inflammation. Central to IFN-γ signaling is Nitric Oxide (NO) synthesis induction by NOS2, a key mediator of its antimicrobial and antitumor activities. This Ph.D. thesis investigates two main aspects of IFN-γ signaling. Firstly, it explores the metabolic reprogramming induced by IFN-γ in tumor cells, emphasizing the modulation of glycolytic flux. Secondly, it identifies novel compounds capable of attenuating IFN-γ-induced NO production, with potential implications for treating inflammatory diseases. In the tumor microenvironment, IFN-γ signaling is critical in tumor suppression by inducing apoptosis and ferroptosis. The metabolic response of tumor cells to IFN-γ stimulation was characterized, revealing enhanced glycolytic activity and lactate production mediated by NO and ROS-dependent mechanisms. Notably, the study demonstrates that IFN-γ-mediated metabolic alterations impact tumor growth and highlights potential therapeutic strategies for cancer immunotherapy. Inflammatory diseases, including ulcerative colitis and sepsis, are associated with excessive IFN-γ-induced NO production. Screening of the LOPAC®1280 library identified several novel compounds capable of inhibiting IFN-γ-induced NO synthesis. Among these, auranofin emerged as a potent inhibitor, significantly reducing NO production and inflammatory cytokine secretion in vitro and in vivo. Furthermore, auranofin and pentamidine exhibited promising therapeutic effects in preclinical ulcerative colitis and sepsis models. This thesis underscores the intricate interplay between IFN-γ signaling, cellular metabolism, and inflammation. The findings offer insights into potential therapeutic avenues for cancer immunotherapy and the treatment of inflammatory disorders. Future research directions include exploring the translational potential of identified compounds and further elucidating their immunomodulatory effects and safety profiles for clinical applications.