Vasoactive intestinal peptide suppresses T cell activation via VPAC1 receptor and limits anti-tumor immunity.

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Presentation Time: 01:45 PM - 02:00 PM
Abstract ID: 5568 - B

Presenting Author:
Tenzin Passang , PhD Student at Winship Cancer Inst., Emory Univ.

Abstract:

Only a fraction of cancer patients respond to current immune checkpoint inhibitors. Our lab has identified vasoactive intestinal peptide receptor (VIPR) signaling as a targetable immune checkpoint pathway in cancer. VIP is a small neuropeptide with known immunosuppressive effects on T cells. However, the role of specific VIP receptors on T cells is currently unknown. Here, we evaluate differences in T cell phenotype using pharmacological and genetic methods to inhibit VIPR pathway in vitro and in mouse models of cancer.  VIP knockout (KO) T cells exhibited augmented activation and cytokine production compared to activated wildtype (WT) T cells. Cite-Seq analysis on KPC.luc tumors showed enrichment of CD8+ cluster 2 following treatment with VIPR antagonist, ANT308, expressing high Ki67 and CDK1. Combination treatment of ANT308 with anti-PD1 therapy led to increased CD8+ cluster 1, which expressed high perforin and granzyme B. PDAC cells engrafted to VIPKO mice had delayed tumor growth rate and prolonged survival compared to WT mice. These findings were confirmed in the tumor-bearing bone marrow chimeric mice where VIP expression was restricted to hematopoietic cells. Furthermore, we found significantly improved anti-tumor response in VPAC1KO mice comparable to VIPKO mice but not in VPAC2KO mice. Overall, we show that VIP signaling via VPAC1 is a novel autocrine checkpoint pathway in activated T cells and represents a potential target for enhancing cancer immunotherapy.