Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Interferons (IFNs) are central orchestrators of tumor immunity and can elicit both pro-tumor and anti-tumor responses depending on the cancer cell type, the type of IFN produced (e.g. a, b or g), duration of the signal, and other factors in the tumor microenvironment (TME). In their anti-tumor role, IFNs induce expression of major histocompatibility complex I (MHC-I) on the surface of tumor cells that mediates CD8+ T cell recognition and killing. Paradoxically, IFNs also upregulate expression of CD8+ T cell inhibitory surface molecules such as programmed death ligand 1 (PD-L1) to temper the immune response and avoid an autoimmune reaction. Thus, IFNs play a dual and opposing role in cancer development, making a more complete understanding of the contexts in which their pro- or anti-tumor functions predominate important for effective cancer therapy development. Immune evasion can occur when malignant cells lose MHC-I and antigen processing and presentation (APP) machinery or otherwise become desensitized to IFN signaling. Thus, finding ways to reinvigorate these pathways has significant therapeutic potential. Interestingly, recent work from the sponsor’s lab and others has shown that mitochondrial electron transport chain activity is required for IFN-induced MHC-I expression. In addition, preliminary data show that chronic IFN stimulation in vitro reduces mitochondrial oxidative phosphorylation (OXPHOS) in melanoma cells, suggesting that IFN signaling can also influence tumor mitochondrial metabolism. To probe this novel regulatory link between the metabolic state of tumor cells and their responses to IFN, a metabolism-targeted CRISPR knock-out screen was performed in mouse melanoma cells. Results from this screen not only confirmed a requirement for mitochondrial OXPHOS in regulating IFN signaling, but also implicated fatty acid metabolism and ROS. Based on these preliminary data, it is proposed that mitochondrial OXPHOS, specifically mitochondrial fuel utilization and ROS production, can directly regulate key IFN signaling steps, and that chronic IFN exposure leads to changes in mitochondrial metabolism that facilitate immune evasion in melanoma. This overall hypothesis will be tested through completion of two specific aims. Aim 1 is to determine which steps in the IFN signaling pathway are subject to mitochondrial OXPHOS- mediated regulation and the precise mitochondrial metabolic signals involved. Aim 2 is to determine how reduced mitochondrial OXPHOS and/or increased mitochondrial ROS are generating a suppressive tumor microenvironment and if chronic type I IFN signaling elicits similar immunosuppressive effects as chronic type II IFN exposure. This project will provide important new insights into the relationship between mitochondrial metabolism and IFN responses during tumor progression that might be exploited to improve or reactivate anti- tumor immune responses for better cancer treatment and augment cancer immunotherapy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
