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Targeting PTGIR-Prostacyclin Signaling to Overcome T Cell Exhaustion and Enhance Anti-Tumor Immunity

Award Number: K99CA293261
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Targeting PTGIR-Prostacyclin Signaling to Overcome T Cell Exhaustion and Enhance Anti-Tumor Immunity - PROJECT SUMMARY Continuous exposure to cancer antigens causes CD8 T cells to become ineffective; a state referred to as CD8 T cell exhaustion (Tex). One hallmark of Tex is the increase in cell surface immune checkpoint proteins that engage in protein-protein interactions with their respective ligands on cancer cells. Immune checkpoint inhibitors (ICIs) intercept these interactions and “reinvigorate” Tex cells, and are now a standard treatment for many cancers. Unfortunately, up to 50% of ICI-treated cancer patients do not respond to treatment or relapse, indicating that there are other mechanisms that enforce T cell exhaustion. The long-term goal of this project is to identify and understand these alternative mechanisms, so we can develop complementary therapies that will deliver more durable clinical responses. To that end, we recently found that hyperactivation of the transcription factor NRF2 (Nuclear factor erythroid 2-related factor 2) upregulates the prostacyclin receptor (PTGIR) to drive Tex in mouse CD8 T cells. Specifically, PTGIR signaling reduces the percentage of cytokine-producing CD8+ tumor infiltrating lymphocytes (TILs), resulting in aggressive growth of mouse tumors. Preliminary in vitro data hint that PTGIR signaling in CD8 T cells may dampen mitochondrial bioenergetics by reducing acetate entry into the TCA cycle. Conversely, patients (and mice) who have elevated levels of prostacyclin synthase, and hence prostacyclin, in their tumors exhibit poor overall survival. These data suggest that the PTGIR:prostacyclin interaction is a novel immune checkpoint that drives mitochondrial dysfunction to enforce Tex. If true, then pharmacologically intercepting PTGIR-prostacyclin signaling in vivo might be a new means of attenuating T cell exhaustion and boosting anti-tumor immunity. These hypotheses will be tested in several inter-related Aims using mouse tumor models. Aim 1 will use a joint RNA-seq/13C metabolomics method to determine how PTGIR drives T cell exhaustion in vivo, thus linking prostacyclin receptor signaling in the TME to intracellular CD8+ TIL mitochondrial dysfunction. Aim 2 will leverage 13C metabolomics to show that cancer cells secrete prostacyclin, and scRNA-seq to show that prostacyclin induces Tex, and an immunosuppressive TME. These data will lay a foundation for developing prostacyclin synthase inhibitors as an adjunct cancer therapy. Aim 3 will test whether repurposing of PTGIR inhibitors that block the PTGIR:prostacyclin checkpoint, can prevent Tex, or rejuvenate an immunosuppressed TME. This project will also help us develop new skills in RNA-seq, scRNA-seq, and in vivo 13C metabolomics, that will be instrumental in establishing an independent lab and career. Accordingly, our future team will be in a strong position to develop and test new immune checkpoint inhibitors that target protein:lipid interactions, which may complement standard-of-care immunotherapies to improve cancer patient survival rates.


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 = $112,234 )
2026	2026	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Research Manpower	000	2	7/14/2026	NON-COMPETING CONTINUATION	$112,234
														Subtotal = $112,234

Issue Date FY: 2025 ( Subtotal = $112,234 )
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Research Manpower	000	1	7/30/2025	NEW	$112,234
														Subtotal = $112,234

Grand Total All Awards = $224,468

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Targeting PTGIR-Prostacyclin Signaling to Overcome T Cell Exhaustion and Enhance Anti-Tumor Immunity

Award Number: K99CA293261

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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