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Modulation of metabolism in TILs by the checkpoint inhibitor PSGL-1

Award Number: R21CA249353
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/18/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2022

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Modulation of metabolism in TILs by the checkpoint inhibitor PSGL-1 - SUMMARY The goal of this project is to address metabolic regulation of exhausted T cells (TEX) by the immune inhibitory receptor (IR), PSGL-1 (P-selectin glycoprotein 1) and to determine if blocking its engagement on T cells can reverse metabolic constraints on tumor infiltrating T cells (TILs) to support antitumor immunity. Effector CD8+ T cells (TEFF) are vital in eliminating tumor cells, including melanoma, but within tumors, T cells become progressively dysfunctional and unable to destroy tumors. Exhaustion is associated with a loss of metabolic fitness and with increased co-expression of IRs, including PD-1, LAG3, TIM3, and CTLA-4. Although immune checkpoint blockade (ICB) of PD-1 and CTLA-4 can reinvigorate TEX and eradicate tumors in some patients, in melanoma, the majority (60%) of patients are refractory to treatment or fail to achieve durable responses. For many other cancers, response rates to ICB are much lower. It is therefore essential to identify novel mechanisms to more broadly induce effective antitumor responses and provide benefit to a far greater number of patients. Recent studies indicate that alterations of T cell metabolism within the tumor microenvironment underlie the development of TEX and their rescue with ICB. Intratumoral T cells can lose mitochondrial function and biogenesis, and exhibit decreased glycolysis and increased fatty acid oxidation. Changes in tumor cell metabolism are also linked with T cell responses, with oxidative tumor cell metabolism linked to increased TEX, and glycolytic tumor cell metabolism coupled to responses to PD-1 blockade. It is therefore critical to identify checkpoint regulators that support T cell metabolic parameters that underlie effective antitumor responses. We discovered that PSGL-1 (Selplg) is a previously unknown T cell intrinsic IR that promotes expression of multiple IRs on CD4+ and CD8+ T cells in the contexts of chronic viral infection and tumors, underscoring an integral connection to immune inhibitory pathways. Our studies suggest that PSGL-1 is a key inducer of the IR gene module that promotes TEX. Importantly, Selplg-/- mice demonstrate dramatic control of melanoma tumors and transfer of PSGL-1-deficient tumor-specific CD8+ T cells is sufficient to significantly delay tumor growth. Our new data show that Selplg-/- CD8+ T cells have increased glycolysis compared to their Selplg+/+ counterparts, and single-cell RNA-sequencing (scRNA-seq) analysis of Selplg-/- CD8+ TILs identified greatly increased expression of several genes associated metabolic function. Thus, we hypothesize that blocking PSGL-1 will provide a mechanism of metabolic reprograming of antitumor T cells and subvert inhibition by multiple IRs, thereby enhancing antitumor responses. To test this scientific premise, we propose to define the intrinsic contribution(s) of PSGL-1 signaling to the antitumor T cell metabolome and to assess whether PSGL-1-targeted ICB promotes metabolic changes in TILs that support effective T cell antitumor responses to melanoma using Seahorse assays and the novel scRNA-seq technique, CITE-seq, to evaluate the interplay between metabolic changes in Selplg-/- CD8+ T cells and melanoma tumor cells.


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: 2022 ( Subtotal = $0 )
2022	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	2	4/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $227,906 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	2	1/29/2021	NON-COMPETING CONTINUATION	$227,906
														Subtotal = $227,906

Issue Date FY: 2020 ( Subtotal = $273,488 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	1	2/18/2020	NEW	$273,488
														Subtotal = $273,488

Grand Total All Awards = $501,394

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Modulation of metabolism in TILs by the checkpoint inhibitor PSGL-1

Award Number: R21CA249353

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/18/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2022

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