# Targeting Checkpoint Inhibition in Anti-Tumor Responses

> **NIH NIH R03** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $97,500

## Abstract

PROJECT SUMMARY
The goal of this project is to evaluate novel therapeutics that block PSGL-1 (P-selectin glycoprotein-1), which
we identified as a key inhibitory receptor (IR) that is expressed on T cells, and address the impact(s) on
immune cell functions in the tumor microenvironment (TME). PSGL-1 is a conserved ligand for the selectin
family of adhesion molecules, P, E, and L, that is expressed on most hematopoietic cells and regulates leukocyte
migration when fully glycosylated. T cells are the only cells that express the non-selectin binding form of PSGL-
1 that serves as a receptor for the lymph node chemokines, CCL19 and CCL21, and the PD-L1 homologue,
VISTA (B7-H5). We showed that PSGL-1-deficient (Selplg-/-) CD8 T cells fail to acquire the hallmarks of
exhaustion compared to their wild-type (WT) counterparts after infection with chronic lymphocytic
choriomeningitis virus and significantly limit tumor growth in two murine models of melanoma, one that is
nonresponsive to anti-PD-1 treatment. We identified that TILs from Selplg-/- mice have greater anti-tumor
function, including cytotoxicity and cytokine production. Moreover, expression of multiple inhibitory receptors
(IRs) that distinguish exhausted T cells (TEX) were downregulated on Selplg-/- T cells, including PD-1, BTLA,
CD160, LAG3, and TIM3. Notably, PSGL-1 ligation on naïve T cells (TN) and TEX by an agonist mAb in the context
of T cell receptor stimulation induced/augmented expression of multiple IRs, underscoring an integral connection
of PSGL-1 to immune inhibitory pathways and suggesting a link to the recently identified inhibitory gene module
that regulates the coordinated transcription of IRs. We identified that a monovalent Fab of the same agonist mAb
dramatically improved T cell responses as did treatment with a rPSGL-1 fusion protein, indicating a capacity to
block PSGL-1 function. Notably, blocking PSGL-1 did not lead to widespread inflammation or toxicity. We
hypothesize that PSGL-1 blockade has the potential to augment anti-tumor T cell responses by limiting
expression levels of multiple IRs, and alter immunosuppression in the TME by impacting other immune
cells. We propose to evaluate the effects of PSGL-1 blockade on mouse and human T cell anti-tumor responses
using rPSGL-1 and Fab anti-PSGL-1 as comparators to novel mouse and human anti-PSGL-1 blocking mAbs.
With these tools, we will analyze the impacts of blocking PSGL-1 on IR expression and functions of T cells and
immune cells in the TME, as well as potential synergy with anti-PD-1. In the context of these studies, we will
assess the role of VISTA as the relevant PSGL-1 ligand in the TME. These studies will address the potential of
targeting PSGL-1 for reversal of T cell exhaustion, induction of anti-tumor immunity, and translational potential.

## Key facts

- **NIH application ID:** 10202111
- **Project number:** 1R03CA252144-01A1
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Linda Mac Pherson Bradley
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $97,500
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202111

## Citation

> US National Institutes of Health, RePORTER application 10202111, Targeting Checkpoint Inhibition in Anti-Tumor Responses (1R03CA252144-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10202111. Licensed CC0.

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