VPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer

Abstract Pancreatic cancer (PDAC) harbors a complex tumor microenvironment (TME), and crosstalk between cells in the TME can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP signaling through VIP receptor 2 (VPAC2). High co-expression of VIP with VPAC2 correlated with reduced relapse-free survival in PDAC patients. VPAC2 activation in PDAC cells upregulated piwi-like RNA-mediated gene silencing 2 (Piwil2), which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGF-β1 to inhibit T cell function. Loss of VPAC2 on PDAC cells led to reduced tumor growth and increased sensitivity to anti-PD1 immunotherapy in mouse models of PDAC. Overall, these findings expand our understanding of the role of VIP/VPAC2 signaling in PDAC and provide the rationale for developing potent VPAC2-specific antagonists for treating PDAC patients.