VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

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.

Unraveling the potential of CD8, CD68, and VISTA as diagnostic and prognostic markers in patients with pancreatic ductal adenocarcinoma

“…Colorectal cancer also demonstrated comparable results, as anti-VISTA therapy proved effective in conquering resistance to anti-PD-1/CTLA-4 treatment ( 66 ). Similar to a recent study ( 103 ), our data confirm that infiltrating immune cells highly express membranous VISTA in human PDAC.…”

The VISTA/VSIG3/PSGL-1 axis: crosstalk between immune effector cells and cancer cells in invasive ductal breast carcinoma

“…VISTA is an immunological checkpoint protein, and its overexpression, together with increased levels of the VSIG3 and PSGL-1 receptors in the tumor microenvironment, may be involved in the modulation of immune responses to cancer. There is growing evidence of the importance of the immunosuppressive role of VISTA in cancer progression [20,41,57,62,63,[69][70][71][72][73]. The presence of VISTA on the surface of cancer cells can not only modulate immune cells but also potentially play a much broader role in cancer biology.…”

Small molecule agents for triple negative breast cancer: Current status and future prospects

“…V-domain Ig suppressor of T-cell activation (VISTA) is an immune checkpoint protein with the capacity to suppress T cell activity [257] , playing a crucial role in anti-tumor immunity. Studies have shown that VISTA is expressed at low levels in TNBC, but it is highly expressed in immune cells within the TME.…”