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

> **NIH NIH R21** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $227,906

## Abstract

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 effec...

## Key facts

- **NIH application ID:** 10110001
- **Project number:** 5R21CA249353-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Linda Mac Pherson Bradley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $227,906
- **Award type:** 5
- **Project period:** 2020-02-18 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110001

## Citation

> US National Institutes of Health, RePORTER application 10110001, Modulation of metabolism in TILs by the checkpoint inhibitor PSGL-1 (5R21CA249353-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10110001. Licensed CC0.

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