PSGL-1 Immune Checkpoint Inhibition for CD4+ T Cell Cancer Immunotherapy

Abstract

Immune checkpoint inhibition targeting T cells has shown tremendous promise in the treatment of many cancer types and are now standard therapies for patients. While standard therapies have focused on PD-1 and CTLA-4 blockade, additional immune checkpoints have shown promise in promoting anti-tumor immunity. PSGL-1, primarily known for its role in cellular migration, has also been shown to function as a negative regulator of CD4+ T cells in numerous disease settings including cancer. PSGL-1 is highly expressed on T cells and can engage numerous ligands that impact signaling pathways, which may modulate CD4+ T cell differentiation and function. PSGL-1 engagement in the tumor microenvironment may promote CD4+ T cell exhaustion pathways that favor tumor growth. Here we highlight that blocking the PSGL-1 pathway on CD4+ T cells may represent a new cancer therapy approach to eradicate tumors.

PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection

“…Naïve T cells lack these modifications and are thus unable to bind selectins, but can acquire selectin binding capacity during effector differentiation ( 11 ), although expression is typically transient. On T cells, however, PSGL-1 can engage additional ligands in the absence of, or independently of selectin binding ( 12 ). These include the lymphoid tissue chemokines, CCL19 and CCL21 ( 13 ), which regulate the entry and positioning of T cells and dendritic cells in secondary lymphoid organs ( 14 ), and VISTA (V-type immunoglobulin domain-containing suppressor of T cell activation) ( 15 ), a negative regulator of T cell responses, which is primarily expressed on myeloid cells ( 16 ), respectively.…”

P-selectin glycoprotein ligand 1 promotes T cell lymphoma development and dissemination

“…We cloned human SELPLG cDNA in a vector containing GFP for expression in EL4.2 cells. Despite differences in amino acid sequence, human and mouse PSGL-1 are functionally conserved, as supported by reports showing PSGL-1 cross-species interactions with selectins [29] , [30] , [31] . After transfection of GFP-expressing empty and PSGL-1-expressing plasmids and serial sorting and culturing of GFP-positive cells (Fig.…”

P-Selectin Glycoprotein Ligand 1: A Potential HIV-1 Therapeutic Target

“…Finally, a recent publication extensively reviewed the role of PSGL-1 in the development of neoplastic disease. The authors reported that blocking the CD4 + T-cell’s PSGL-1 pathway could possibly be utilized as a novel cancer therapeutic approach to treat tumors ( 98 ). Indeed, PSGL-1 activation in the tumor microenvironment can promote CD4 + T-cell exhaustion pathways, which promotes tumor development.…”

“…Secondly, PSGL-1 is an HIV restriction factor, and as such, its expression is triggered by interferon-γ, an immunomodulatory cytokine whose role in innate immunity in HIV infection has only begun to be elucidated ( 109 , 110 ). Additionally, IL-12 (using Th1 cells from mice) ( 98 ), soluble CD40 ligand (sCD40L, using monocytes from HIV negative donor) ( 104 ), and glutamate (using monocytes from HIV negative donor) ( 104 ) have been proven to be capable of inducing PSGL-1 expression ex vivo . Thus, interferon-γ or IL-12 administration in combination with strategies such as ART, immunotherapy, and gene therapy may provide substantial improvement in the immune responses of HIV-infected individuals.…”

“…treat tumors (98). When the HIV virion has found target cells (CD4 T-cells), the virus surface glycoprotein (gp120) binds to a cell receptor or coreceptors such as chemokine CC receptor 5 (CCR5) or chemokine CXC receptor 4 (CXCR4), also responsible for the HIV entry into lymphocytes and macrophages.…”