DeRogatis et al. investigated the role of PSGL-1 in the TME using several aggressive mouse melanoma models (B16-GP33 and D4M-3A) that are largely non-responsive to therapies targeting PD-1. Anti-PSGL-1 treatment delayed tumor growth and resulted in increased CD4+ and CD8+ T cell proliferation, with increased activation and effector function, while Treg numbers decreased in tumors. The combination with anti-PD-1 enhanced antitumor immunity, and in PSGL-1-deficient mice, anti-PD-1 treatment led to a significant increase in tumor-free mice, nominating PSGL-1 as a new targetable checkpoint for melanoma treatment.
Contributed by Katherine Turner
ABSTRACT: Immune checkpoint inhibitors have had impressive efficacy in some cancer patients, reinvigorating long-term durable immune responses against tumors. Despite the clinical success of these therapies, most cancer patients continue to be unresponsive to these treatments, highlighting the need for novel therapeutic options. Although P-selectin glycoprotein ligand-1 (PSGL-1) has been shown to inhibit immune responses in a variety of disease models, previous work has yet to address whether PSGL-1 can be targeted therapeutically to promote antitumor immunity. Using an aggressive melanoma tumor model, we targeted PSGL-1 in tumor-bearing mice and found increased effector CD4+ and CD8+ T-cell responses and decreased regulatory T cells (Tregs) in tumors. T cells exhibited increased effector function, activation, and proliferation, which delayed tumor growth in mice after anti-PSGL-1 treatment. Targeting PD-1 in PSGL-1-deficient, tumor-bearing mice led to an increased frequency of mice with complete tumor eradication. Targeting both PSGL-1 and PD-1 in wild-type tumor-bearing mice also showed enhanced anti-tumor immunity and slowed melanoma tumor growth. Our findings showed that therapeutically targeting the PSGL-1 immune checkpoint can reinvigorate anti-tumor immunity and suggest that targeting PSGL-1 may represent a new therapeutic strategy for cancer treatment.
Author Info: (1) University of California, Irvine, Irvine, CA, United States. (2) University of California, Irvine, Irvine, CA, United States. (3) University of California, Irvine, Irvine, CA,
Author Info: (1) University of California, Irvine, Irvine, CA, United States. (2) University of California, Irvine, Irvine, CA, United States. (3) University of California, Irvine, Irvine, CA, United States. (4) University of California, Irvine, Irvine, CA, United States. (5) University of California, Irvine, Irvine, CA, United States. (6) University of California, Irvine, Irvine, CA, United States.
