VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

SIMPLE SUMMARY: The V-domain Ig suppressor of T-cell activation (VISTA) suppresses T-cell effector function, and has been investigated as an alternative immunotherapeutic target in several cancers. In this study, we found increased VISTA expression in pancreatic tumor cells to be associated with decreased overall survival. Immune cells also expressed VISTA, and interaction with tumors cells further enhanced their VISTA expression. Recombinant VISTA inhibited proinflammatory T-cell function and cytokine production. In a syngeneic orthotopic model, VISTA-blockade resulted in decreased tumor weights. VISTA is a potential target that may be included in immunotherapeutic strategies for the treatment of PDAC. ABSTRACT: Immunotherapy has shown promising results in multiple solid tumors and hematological malignancies. However, pancreatic ductal adenocarcinoma (PDAC) has been largely refractory to current clinical immunotherapies. The V-domain Ig suppressor of T-cell activation (VISTA) inhibits T-cell effector function and maintains peripheral tolerance. Here, we determine VISTA expression in nontumorous pancreatic (n = 5) and PDAC tissue using immunohistochemistry (n = 76) and multiplex immunofluorescence staining (n = 67). Additionally, VISTA expression on tumor-infiltrating immune cells and matched blood samples (n = 13) was measured with multicolor flow cytometry. Further, the effect of recombinant VISTA on T-cell activation was investigated in vitro, and VISTA blockade was tested in an orthotopic PDAC mouse model in vivo. PDAC showed significantly higher VISTA expression compared to that of a nontumorous pancreas. Patients with a high density of VISTA-expressing tumor cells had reduced overall survival. The VISTA expression of CD4(+) and CD8(+) T cells was increased after stimulation and particularly after a coculture with tumor cells. We detected a higher level of proinflammatory cytokine (TNFα and IFNγ) expression by CD4(+) and CD8(+) T cells, which was reversed with the addition of recombinant VISTA. A VISTA blockade reduced tumor weights in vivo. The VISTA expression of tumor cells has clinical relevance, and its blockade may be a promising immunotherapeutic strategy for PDAC.