VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

Cancers · 14 authors, 9 centres

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TL;DR

This study analyzed VISTA expression in human pancreatic cancer samples and tested its function in cell and mouse models. It found high tumor-cell VISTA expression correlates with worse patient survival and that blocking VISTA reduced tumor growth in a mouse model.

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The study investigated the role of the immune checkpoint protein VISTA in pancreatic ductal adenocarcinoma (PDAC). Researchers analyzed VISTA expression in human PDAC tissue and tumor-infiltrating immune cells using immunohistochemistry, multiplex immunofluorescence, and flow cytometry. They found significantly higher VISTA expression in PDAC compared to normal pancreas, and high VISTA expression on tumor cells was associated with reduced overall survival. In vitro, recombinant VISTA inhibited proinflammatory cytokine production by T cells. In a syngeneic orthotopic PDAC mouse model, VISTA blockade resulted in decreased tumor weights. Limitations include the use of a mouse model and a single human PDAC cell line. The findings suggest VISTA on tumor cells is a clinically relevant mechanism of immune suppression and a potential immunotherapeutic target for PDAC.

STUDY TYPE

other

SPECIALTY

oncology

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100% · A

ORIGINAL PAPER

PMC10136841

VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

Cancers

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ABSTRACT

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.

CITATION EXPORT

David Digomann, Johannes Strack, Max Heiduk et al.. VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer. Cancers. (2023). https://doi.org/10.3390/cancers15082326

AUTHORS

14 · 9 CENTRES

David Digomann, Johannes Strack, Max Heiduk, Ioana Plesca, Luise Rupp, Charlotte Reiche, Simone Nicolaus, Carolin Beer, Ulrich Sommer, Marc Schmitz, Marius Distler, Jürgen Weitz, Adrian M. Seifert, Lena Seifert

1Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
2National Center for Tumor Diseases (NCT/UCC), 01307 Dresden, Germany
3German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
4Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
5Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01328 Dresden, Germany
6Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
7Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
8German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Dresden, 69120 Heidelberg, Germany
9Else Kröner Clinician Scientist Professor for “Translational Tumor Immunological Research”, 01307 Dresden, Germany

EDITOR / REVIEWER

Cosimo Sperti