biostudies-literaturePassang TAbraham J. and Phyllis Katz Foundation (Katz Foundation)Abraham J. and Phyllis Katz FoundationNCI NIH HHS2954-2967https://www.ebi.ac.uk/biostudies/studies/S-EPMC11458156biostudies-literatureUnknown84(18)Pancreatic ductal adenocarcinoma (PDAC) harbors a complex tumor microenvironment, and cross-talk among cells in the tumor microenvironment 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 coexpression of VIP with VPAC2 correlated with reduced relapse-free survival in patients with PDAC. VPAC2 activation in PDAC cells upregulated Piwi-like RNA-mediated gene silencing 2, which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGFβ1 to inhibit T-cell function. Loss Cancer researchVPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer.PMC11458156R01 CA287866Liu YPassang TWang SZhang HRavindranathan SLi JMWang WZeng FWaller EKHsu PCLesinski GBfalseVPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer.Pancreatic ductal adenocarcinoma (PDAC) harbors a complex tumor microenvironment, and cross-talk among cells in the tumor microenvironment 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 coexpression of VIP with VPAC2 correlated with reduced relapse-free survival in patients with PDAC. VPAC2 activation in PDAC cells upregulated Piwi-like RNA-mediated gene silencing 2, which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGFβ1 to inhibit T-cell function. Loss 2024-01-01T00:00:00Z2024 Sep2026-06-01T07:18:22.77Z2025-04-06T22:46:11.093ZS-EPMC114581563880969410.1158/0008-5472.can-23-362810.1158/0008-5472.CAN-23-3628