Biology subjects

Palete, A. B.

Publications and source records attributed to Palete, A. B..

2 recordsLinked to original sources

bioRxiv2025

Disabling PSGL-1 abrogates immune suppression and resistance to PD-1 blockade in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer for which there is a critical need to identify novel therapeutic targets. Herein we define PSGL-1 as a checkpoint inhibitor using a syngeneic orthotopic model of PDAC. As with PDAC patients, CD8+ T cells within murine PDAC tumors expressed high levels of PSGL-1. PSGL-1-/- mice displayed striking T cell-dependent control of primary tumors and lung metastases. Extensive spatial remodeling within PDAC tumors occurred in PSGL-1-/- mice with a dramatic loss of proliferating tumor cells and an increase in CD8+ T cell engagement of antigen-presenting cells. The prominent CD8+ T cell infiltrates included subsets of pre-exhausted T cells retaining hallmarks of stemness and multifunctional effector capacity. These changes enabled a near complete response of PDAC to therapeutic PD-1 blockade. Our findings identify PSGL-1 as a key regulator of anti-tumor immunity in PDAC, highlighting its potential as a therapeutic target to limit CD8+ T cell exhaustion and enhance immunotherapy response. SummaryHope et al describe a pivotal function of PSGL-1 in CD8+ T cell responses to pancreatic ductal adenocarcinoma. Genetic deletion of PSGL-1 elicits tumor control by increasing T cell infiltration and maintaining functional subsets, thereby promoting sensitivity to PD-1 blockade.

immunology↗

bioRxiv2022

PSGL-1 directs early TCR signaling to repress metabolism and promote T cell exhaustion by modulating the TCF-1/TOX axis in CD8+ T cells.

Summary/AbstractWe previously identified the adhesion molecule PSGL-1 as a T cell intrinsic immune checkpoint regulator of T cell exhaustion. Here we show that the ability of PSGL-1 to restrain TCR sginaling correlates with decreased expression of the Zap70 inhibitor Ubash3b (Sts-1) in PSGL-1-deficient T cells. PSGL-1-deficency in T cells supports antitumor responses to a PD-1 blockade resistant melanoma wherein tumor-specific CD8+ T cells sustain an enhanced metabolic state, with an elevated metabolic gene signature that promotes increased glycolysis and glucose uptake to support effector functions. In models of chronic virus infection and cancer, this outcome was associated with CD8+ T cell stemness, as PSGL-1 deficient CD8+ T cells displayed increased TCF-1 and decreased TOX expression, a phenotype shown to be crucial for responsiveness to checkpoint inhibition. Further, we demonstrate that PSGL-1 signaling promotes development of exhaustion in human CD8+ T cells. Finally, pharmacologic blockade of PSGL-1 was sufficient to curtail T cell exhaustion and enhance functionality both with melanoma tumors and chronic LCMV infection, demonstrating that PSGL-1 represents a therapeutic target for immunotherapy for PD-1/PD-L1 resistant tumors.

immunology↗