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V-domain Ig suppressor of T cell activation (VISTA) is a potent negative regulator of T-cell function that is expressed on hematopoietic cells. VISTA levels are heightened within the tumor microenvironment, in which its blockade can enhance antitumor immune responses in mice. In humans, blockade of the related programmed cell death 1 (PD-1) pathway has shown great potential in clinical immunotherapy trials. Here, we report the structure of human VISTA and examine its function in lymphocyte negative regulation in cancer. VISTA is expressed predominantly within the hematopoietic compartment with highest expression within the myeloid lineage. VISTA-Ig suppressed proliferation of T cells but not B cells and blunted the production of T-cell cytokines and activation markers. Our results establish VISTA as a negative checkpoint regulator that suppresses T-cell activation, induces Foxp3 expression, and is highly expressed within the tumor microenvironment. By analogy to PD-1 and PD-L1 blockade, VISTA blockade may offer an immunotherapeutic strategy for human cancer.

Original publication

DOI

10.1158/0008-5472.can-13-1504

Type

Journal article

Journal

Cancer research

Publication Date

04/2014

Volume

74

Pages

1924 - 1932

Addresses

Authors' Affiliations: Medical Research Council Centre of Transplantation, Guy's Hospital, King's College London, King's Health Partners; Department of Immune Regulation and Intervention, King's College London, London, United Kingdom; Department of Medicine, Geisel School of Medicine at Dartmouth; Department of Microbiology and Immunology, Dartmouth Medical School; and Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Keywords

T-Lymphocytes, Animals, Mice, Inbred C57BL, Humans, Mice, Immunoglobulins, Lymphocyte Activation, Female, Antigens, CD274, B7 Antigens