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Abstract B033: Leveraging PSGL-1 blockade to elicit responses to anti-PD-1 immunotherapy resistant melanoma
Abstract   Peer reviewed

Abstract B033: Leveraging PSGL-1 blockade to elicit responses to anti-PD-1 immunotherapy resistant melanoma

Hannah A.F. Hetrick, Evelyn S. Sanchez-Hernandez, Brianna J. Robinson, Mahary Lalarizo Rakoto, Laura Cort, Jennifer L. Hope and Linda M. Bradley
Cancer immunology research, v 14(2_Supplement), pp B033-B033
18 Feb 2026
DOI: https://doi.org/10.1158/2326-6074.IO2026-B033

Abstract

With the high incidence of anti-PD-1 resistant melanoma, there is a current clinical focus on using combinatorial treatment strategies to improve patient outcomes. Our previous studies showed that PSGL-1 (P-selectin glycoprotein-1) is a fundamental T cell intrinsic inhibitory receptor that acts upstream of PD-1 to drive T cell functional exhaustion. Genetic disabling of PSGL-1 supported significant tumor growth control in YUMM1.5, an anti-PD-1 resistant murine melanoma model, by enhancing the infiltration and preservation of responses by CD8+ T cells within the tumors. In this study we developed a novel PSGL-1 blocking antibody and assessed its effects as a single agent and in combination with anti-PD-1. We administered anti-PSGL-1 systemically from the time of subcutaneous tumor cell inoculation to support the preservation of infiltrating T cells with effector capacity that are deemed necessary for effective PD-1 blockade, thus providing a novel context for evaluating a therapeutic response to anti-PD-1 with established tumors. The tumors and tumor draining lymph nodes (TDLN) were collected for CD8+ T cell and total tumor immune cell profiling by flow cytometry at tumor endpoint. While anti-PSGL-1 or anti-PD-1 treatment alone did not result in a change in tumor burden, the combination achieved a significant reduction in tumor growth. Within the tumors, dual treatment elicited an increase in the numbers of infiltrating CD8+ T cells that were predominantly PD-1+ TCF1- TOX+ and which maintained functional capacity as measured by effector cytokine production. By evaluating CD8+ T cells in the TDLN at day 18 after tumor cell injection, prior to PD-1 blockade, we found that anti-PSGL-1 induced a significant increase in their activation as measured by expression of CD25, CD69 and PD-1. This was confirmed to be a T cell intrinsic effect in vitro where anti-PSGL-1 treatment of isolated CD8+ T cells that were then activated by TCR engagement via anti-CD3 showed induction of these activation markers. Notably, our in vivo studies demonstrated that anti-PD-1 treatment alone and anti-PD-1 + anti-PSGL-1 in combination increased the proportion of PD-1+ TCF1- TOX+ CD8+ T cells signifying greater progression to an exhaustion phenotype in the TDLN, whereas anti-PSGL-1 treatment alone did not. We conclude that PSGL-1 blockade increased the availability of activated but not fully exhausted CD8+ T cells in the TDLNs and supported their egress into tumors, thereby enabling greater responses to anti-PD-1 treatment and attendant tumor control. Our data support that PSGL-1 is a novel target for promoting anti-tumor responses in patients with PD-1 ICB resistant tumors.

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