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

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Abstract
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: Ad-VISTA immunization markedly potentiated the therapeutic efficacy of CAIX-targeted vaccination, resulting in significant tumor growth inhibition and prolonged survival across multiple renal carcinoma models. Mechanistically, VISTA-targeting remodeled the tumor microenvironment by enhancing the infiltration and activation of dendritic cells (DCs) and CD8 + T cells while reducing immunosuppressive myeloid cells and Tregs. Ad-VISTA/CAIX co-immunization promoted the expansion and maturation of multiple DC subsets, characterized by increased expression of CD40, CD80, CD86, and major histocompatibility complex molecules, thereby facilitating efficient antigen presentation. VISTA immunization elicited robust antigen-specific antibody and neutralizing responses, restored CD8 + T-cell proliferation, and enhanced CTL-mediated tumor cell killing. Depletion of CD8 + T cells abrogated therapeutic efficacy of Ad-VISTA/CAIX vaccine, establishing its essential role in tumor control. Furthermore, combined vaccination induced durable memory CD8 + T-cell responses capable of preventing tumor recurrence on rechallenge. Conclusions: These results indicated that vaccine-induced VISTA blockade effectively amplifies DC-mediated CD8 + T-cell immunity and synergistically enhances tumor vaccine efficacy. Targeting VISTA represents a promising immunotherapeutic strategy for improving vaccine-based treatments in renal carcinoma.
Funding Information
  • National Natural Science Foundation of China (82403861)
  • Jiangsu Province Capability Improvement Project through Science, Technology and Education (CXZX202234)
  • Natural Science Research of Jiangsu Higher Education Institutions of China (22KJA320004)
  • Natural Science Foundation of Jiangsu Province (BK20241039)

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