Targeting the PSGL-1 Immune Checkpoint Promotes Immunity to PD-1–Resistant Melanoma

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.

The Treatment of Advanced Melanoma: Therapeutic Update

“…Immune checkpoint inhibitors are drugs which act through the blockage of small proteins produced by immune cells and cancer cells called “ checkpoints ” [ 8 , 9 ]. In particular, programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) are checkpoints which downregulate T cell activation, produced by cancer cells in order to escape from immunity system, producing immune tolerance [ 8 , 9 ].…”

“…Immune checkpoint inhibitors are drugs which act through the blockage of small proteins produced by immune cells and cancer cells called “ checkpoints ” [ 8 , 9 ]. In particular, programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) are checkpoints which downregulate T cell activation, produced by cancer cells in order to escape from immunity system, producing immune tolerance [ 8 , 9 ]. The binding of PD-1, also known the cluster of differentiation 279 (CD279), which is expressed on the surface of monocytes, T cells, and B and NK cells, to its ligand PDL-1 promotes the apoptosis of T cells and activates the regulatory T cells, thus preventing the inflammation pathway [ 8 , 9 ].…”

“…In particular, programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) are checkpoints which downregulate T cell activation, produced by cancer cells in order to escape from immunity system, producing immune tolerance [ 8 , 9 ]. The binding of PD-1, also known the cluster of differentiation 279 (CD279), which is expressed on the surface of monocytes, T cells, and B and NK cells, to its ligand PDL-1 promotes the apoptosis of T cells and activates the regulatory T cells, thus preventing the inflammation pathway [ 8 , 9 ]. CTLA-4, also known as CD152, is constitutively expressed in regulatory T cells and inhibits the activation of T cells [ 8 , 9 ].…”

“…The binding of PD-1, also known the cluster of differentiation 279 (CD279), which is expressed on the surface of monocytes, T cells, and B and NK cells, to its ligand PDL-1 promotes the apoptosis of T cells and activates the regulatory T cells, thus preventing the inflammation pathway [ 8 , 9 ]. CTLA-4, also known as CD152, is constitutively expressed in regulatory T cells and inhibits the activation of T cells [ 8 , 9 ]. Targeting these pathways is a valuable weapon to reduce melanoma immune escape.…”

The Roles of TNFR2 Signaling in Cancer Cells and the Tumor Microenvironment and the Potency of TNFR2 Targeted Therapy

“…Similar data confirmed this is the setting of anti-PD1 therapy with pembrolizumab, even after one cycle of therapy. Tregs were abundant in the TME of humans with metastatic melanoma and retained their immunosuppressive phenotype and functionality following anti-PD-1 [ 96 ]. Epigenetic, transcriptomic, and proteomic analysis of Tregs after immune checkpoint therapies implicated TNFR2 signaling as a possible driver of CD8 + T cell suppression.…”