Psgl-1 modulators and uses thereof

Abstract

The present invention relates to the seminal discovery that P-selectin glycoprotein ligand-1 (PSGL-1) modulates the immune system and immune responses. Specifically, the present invention provides PSGL-1 agonists and antagonists which increase the survival of multifunctional T cells and viral clearance. The present invention further provides methods of treating infectious diseases, cancer and immune and inflammatory diseases and disorders using a PSGL-1 modulator.

1 - 30 . (canceled) 
     
     
         31 . A method of treating a T-cell-mediated disease or disorder comprising administering a P-selectin glycoprotein ligand-1 (PSGL-1) antagonist to a subject in need thereof, wherein the T-cell-mediated disease or disorder is a cancer, wherein the PSGL-1 antagonist increases a CD4+-T-cell-dependent CD8+ T-cell response, and wherein the CD4+ T-cell or CD8+ T-cell express PSGL-1. 
     
     
         32 . The method of  claim 31 , wherein the cancer is selected from the group consisting of prostate, colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, and urogenital tract. 
     
     
         33 . The method of  claim 31 , wherein the PSGL-1 antagonist is an antibody, a small molecule, a protein, a fusion protein or a nucleic acid. 
     
     
         34 . The method of  claim 33 , wherein the antibody is a monoclonal antibody, chimeric antibody, human antibody, or humanized antibody. 
     
     
         35 . The method of  claim 31 , wherein expression of FoxP3, IL-10, TGF-β, and/or MHC class II is increased. 
     
     
         36 . The method of  claim 31 , wherein secretion of IFNγ, TNFα, and CD107 from CD8+ T-cells is increased, or wherein expression of CD25 and T-bet is increased. 
     
     
         37 . The method of  claim 31 , wherein expression of PD-1, BTLA, and CD160 is decreased or increased. 
     
     
         38 . A method of eliciting a T-cell response comprising administering a PSGL-1 antagonist to a subject in need thereof, wherein the PSGL-1 antagonist increases a CD4+-T-cell-dependent CD8+ T-cell response, and wherein the CD4+ T-cell or CD8+ T-cell express PSGL-1. 
     
     
         39 . The method of  claim 38 , wherein the subject has a cancer. 
     
     
         40 . The method of  claim 38 , wherein the PSGL-1 antagonist is an antibody, a small molecule, a protein, a fusion protein or a nucleic acid. 
     
     
         41 . The method of  claim 40 , wherein the antibody is a monoclonal antibody, chimeric antibody, human antibody, or humanized antibody. 
     
     
         42 . The method of  claim 38 , wherein expression of FoxP3, IL-10, TGF-β, and/or MHC class II is increased. 
     
     
         43 . The method of  claim 38 , wherein secretion of IFNγ, TNFα, and CD107 from CD8+ T-cells is increased, or wherein expression of CD25 and T-bet is increased. 
     
     
         44 . The method of  claim 38 , wherein expression of PD-1, BTLA, and CD160 is decreased or increased. 
     
     
         45 . A method of restoring T-cell function comprising administering a P-selectin glycoprotein ligand-1 (PSGL-1) antagonist to a subject in need thereof, wherein the PSGL-1 antagonist increases a CD4+ -T-cell dependent CD8+ T-cell response, and wherein the CD4+ T-cell or CD8+ T-cell express PSGL-1. 
     
     
         46 . The method of  claim 45 , wherein the subject has a cancer. 
     
     
         47 . The method of  claim 45 , wherein the PSGL-1 antagonist is an antibody, a small molecule, a protein, or a nucleic acid. 
     
     
         48 . The method of  claim 47 , wherein the antibody is a monoclonal antibody, chimeric antibody, human antibody, or humanized antibody. 
     
     
         49 . The method of  claim 45 , wherein expression of FoxP3, IL-10, TGF-β, and/or MHC class II is increased, wherein secretion of IFNγ, TNFα, and CD107 from CD8+ T-cells is increased, or wherein expression of CD25 and T-bet is increased. 
     
     
         50 . The method of  claim 45 , wherein expression of PD-1, BTLA, and CD160 is increased or decreased.