title: VISTA Regulates the Development of Protective Antitumor Immunity.
abstract: V-domain Ig suppressor of T-cell activation (VISTA) is a novel negative checkpoint ligand that is homologous to PD-L1 and suppresses T-cell activation. This study demonstrates the multiple mechanisms whereby VISTA relieves negative regulation by hematopoietic cells and enhances protective antitumor immunity. VISTA is highly expressed on myeloid cells and Foxp3(+)CD4(+) regulatory cells, but not on tumor cells within the tumor microenvironment (TME). VISTA monoclonal antibody (mAb) treatment increased the number of tumor-specific T cells in the periphery and enhanced the infiltration, proliferation, and effector function of tumor-reactive T cells within the TME. VISTA blockade altered the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells within the tumor microenvironment. In addition, VISTA blockade impaired the suppressive function and reduced the emergence of tumor-specific Foxp3(+)CD4(+) regulatory T cells. Consequently, VISTA mAb administration as a monotherapy significantly suppressed the growth of both transplantable and inducible melanoma. Initial studies explored a combinatorial regimen using VISTA blockade and a peptide-based cancer vaccine with TLR agonists as adjuvants. VISTA blockade synergized with the vaccine to effectively impair the growth of established tumors. Our study therefore establishes a foundation for designing VISTA-targeted approaches either as a monotherapy or in combination with additional immune-targeted strategies for cancer immunotherapy.
authors.affiliation: Authors' Affiliations: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, The Norris Cotton Cancer Center; ImmuNext Inc., Lebanon, New Hampshire; and Medical Research Council Centre of Transplantation, Guy's Hospital and Department of Immune Regulation and Intervention, King's College London, King's Health Partners, London, United Kingdom.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Mercier
authors.forename: Wenna
authors.initials: W
authors.lastname: Chen
authors.forename: Janet L
authors.initials: JL
authors.lastname: Lines
authors.forename: Maria
authors.initials: M
authors.lastname: Day
authors.forename: Jiannan
authors.initials: J
authors.lastname: Li
authors.forename: Petra
authors.initials: P
authors.lastname: Sergent
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D060887:B7 Antigens / Q000502:physiology*; D019496:Cancer Vaccines / Q000627:therapeutic use; D007136:Immunoglobulins / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D060887:B7 Antigens; D019496:Cancer Vaccines; D007136:Immunoglobulins; C000588758:VSIR protein, human