VISTA neutralization by immunization reprograms immunosuppression and augments vaccine efficacy in renal carcinoma

BACKGROUND: Renal carcinoma remains a highly lethal malignancy, and tumor vaccine efficacy is frequently hampered by a profoundly immunosuppressive tumor microenvironment. V-domain Ig suppressor of T-cell activation (VISTA), an inhibitory immune checkpoint enriched in myeloid cells and regulatory T cells (Tregs), represents a critical barrier to effective antitumor immunity. Targeting VISTA may therefore provide a promising strategy to overcome immune suppression and enhance tumor vaccine efficacy. METHODS: Recombinant adenoviral vaccines encoding carbonic anhydrase IX (CAIX) and VISTA (Ad-CAIX and Ad-VISTA) were constructed and validated for efficient antigen expression. The antitumor efficacy of Ad-VISTA/CAIX co-immunization was evaluated in subcutaneous, lung metastatic, orthotopic, and anti-programmed cell death protein 1-resistant renal carcinoma models. Vaccine-induced immune responses were assessed by flow cytometry, immunohistochemistry, ELISA, cell proliferation assays, cytotoxic T lymphocyte (CTL) assays, and in vivo immune cell depletion experiments. RESULTS: T-cell responses capable of preventing tumor recurrence on rechallenge. CONCLUSIONS: T-cell immunity and synergistically enhances tumor vaccine efficacy. Targeting VISTA represents a promising immunotherapeutic strategy for improving vaccine-based treatments in renal carcinoma.