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Abstract B043: IInhibition of PSGL-1 overcomes immune suppression and immunotherapy resistance in PDAC
Abstract   Peer reviewed

Abstract B043: IInhibition of PSGL-1 overcomes immune suppression and immunotherapy resistance in PDAC

Evelyn S. Sanchez Hernandez, Jennifer L. Hope, Yijuan Zhang, Hannah A.F. Hetrick, Beatrice Silvestri, Brianna J. Smith, Sanmati H. Nakil, Sreeja Roy, Cosimo Commisso and Linda M. Bradley
Cancer immunology research, v 14(2_Supplement), pp B043-B043
18 Feb 2026
DOI: https://doi.org/10.1158/2326-6074.IO2026-B043

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that is resistant to all current treatments including immunotherapies. Cytotoxic CD8+ T cells that eradicate tumor cells are critical for responses against cancer. The PDAC tumor microenvironment (TME) is notoriously immunologically cold, in part driven by limited priming of tumor-specific CD8+ T cells. These T cells poorly infiltrate tumors and become functionally exhausted when confronted with elevated frequencies of suppressive myeloid cells. The poor patient prognosis underscores the urgent need to develop novel therapies to improve patient outcomes. We identified PSGL-1 as a T cell intrinsic checkpoint inhibitor that drives T cell functional exhaustion upstream of PD-1. Thus, we hypothesized that PSGL-1-mediated suppression of CD8+ T cells is a critical barrier to anti-tumor immunity in PDAC. In support of a role for PSGL-1 in PDAC, by interrogation of public databases, we found that high expression of PSGL-1 in patient PDAC tumors is associated with poor survival outcomes. With a murine syngeneic orthotopic model of PDAC using KPC tumor cells, we show that genetic deletion of PSGL-1 enabled significant control of primary tumors at day 26 after injection. This outcome was accompanied by much greater CD8 T cell infiltration when compared to tumors from C57BL/6 controls. By antibody depletion, we establish that this response is T cell dependent. Notably, we identified significantly decreased metastatic burden in PSGL-1-/- mice as assessed by tumor cell clusters in the lungs. Using i.v. tumor injection, we show this to be a direct effect on metastases rather than an indirect consequence of primary tumor size. By spatial proteomic analyses (multiplexed fluorescence histology), we observed extensive remodeling of the PDAC TME in PSGL-1-/- mice at day 21 after tumor injection when tumors were comparable in size in control and PSGL-1-/- mice. This spatial reorganization supported CD8+ T cell engagement of antigen-presenting cells and loss of proliferating tumor cells, suggesting an effective cytotoxic T cell response. Using high dimensional flow cytometry, we identify that the prominent CD8+ T cell infiltrates included subsets of T cells that escape exhaustion, retaining hallmarks of stemness and multifunctional effector capacity. These changes enabled complete responses of PDAC to therapeutic PD-1 blockade administered systemically in 3 doses after tumor growth was established. We conclude that disabling the single inhibitory receptor, PSGL-1, is sufficient to overcome key barriers to PDAC control by promoting CD8+ T cell infiltration, maintaining key CD8+ T cell subsets, rewiring immune cell cross-talk, curtailing metastases, and sanctioning tumor eradication with PD-1 blockade. Our findings establish that immune suppression in PDAC can be overcome and demonstrate that PSGL-1 is a novel potential target to achieve this goal particularly in combination with therapeutic inhibition of PD-1.

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