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Mitochondrial Regulation of Interferon Response in Melanoma

Award Number: F31CA278581
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025
AWARD TERMINATION DATE: 02/12/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$19,168 )
2026	2025	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	3	2/12/2026	TERMINATION	-$19,168
														Subtotal = -$19,168

Issue Date FY: 2025 ( Subtotal = $42,360 )
2025	2025	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	3	7/23/2025	NON-COMPETING CONTINUATION	$42,360
														Subtotal = $42,360

Issue Date FY: 2024 ( Subtotal = $41,796 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	2	7/29/2024	NON-COMPETING CONTINUATION	$41,796
														Subtotal = $41,796

Issue Date FY: 2023 ( Subtotal = $40,516 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	001	1	7/14/2023	NEW	$0
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	1	7/14/2023	NEW	$40,516
														Subtotal = $40,516

Grand Total All Awards = $105,504

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Mitochondrial Regulation of Interferon Response in Melanoma

Award Number: F31CA278581

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

AWARD TERMINATION DATE: 02/12/2026

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