Mitochondrial Regulation of Interferon Response in Melanoma - 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.
