Abstract 5571: Turning up the heat on pancreatic ductal adenocarcinoma via inhibiting vasoactive intestinal peptide signaling
Authors: Ravindranathan Sruthi , Ware Brandon , Zaidi Mohammad , Zhu Jingru , Dhamsania Rohan K. , Wang Shuhua , Li Yiwen , Rao Ishani H. , Thomas Susan N. , Lesinski Gregory B. , El-Rayes Bassel , Waller Edmund K. 
Published: September 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) constitutes more than 90% of all pancreatic cancers and has a 5-year survival rate of only 5-7%. A dense stroma, an immunosuppressive tumor microenvironment (TME) and scarce tumor infiltrating T cells, contribute toward the poor responsiveness of PDAC to conventional and FDA-approved checkpoint therapies. In this study, we show that vasoactive intestinal peptide (VIP) signaling is a novel immune checkpoint pathway in PDAC, which when inhibited in combination with anti-PD1 checkpoint inhibitor, significantly decreases tumor burden and enhances T cell infiltration in mouse models of PDAC.
VIP is a 28-amino acid neuropeptide secreted at the nerve terminals, pancreas and the GI tract, and is commonly associated with regulating gut motility and blood pressure. Interestingly, VIP is also secreted by immune cells and is known to have immunosuppressive properties such as decreasing T cell proliferation and polarizing T cells towards Th2 phenotype. Intriguingly, according to the cancer genome atlas (TCGA), human exocrine pancreatic cancers expresses the highest level of VIP mRNA expression when compared to other solid malignancies. Similarly, we have generated preliminary data that shows enhanced VIP levels both systemically and locally in mouse models of PDAC and in human PDAC patients. Thus, taking all this into consideration, we hypothesized that enhanced VIP signaling is a potential mechanism of immune escape in PDAC and that inhibiting VIP signaling either alone or in combination with checkpoint inhibitors would significantly enhance treatment response in mouse models of PDAC.
We tested the effect of inhibiting VIP signaling by using a VIP receptor antagonist (VIPR antagonist) in orthotopic mouse models of PDAC, where luciferase transfected KPC cells (mouse PDAC cell line), were implanted in the tail of the pancreas. Mice were then treated with VIPR antagonist and/or anti-PD1 seven days after tumor implantation. Our results showed that the combination treatment significantly reduced tumor burden and growth rate, as well as, enhanced the infiltration of both CD4+ and CD8+ T cells into the tumor microenvironment (as per immunohistochemistry of tumor tissues). Furthermore, analysis of tumor infiltrating T cells via Nanostring analysis showed that the combination treatment also significantly enhanced levels of IFN gamma and TNF alpha secreting T cells and costimulatory and effector molecules, including CD27 and FasL.
In summary, we have identified that VIP signaling is a novel and targetable immune checkpoint pathway in PDAC, which when inhibited in combination with checkpoint inhibitors, significantly improves treatment response in mouse PDAC models. As the VIP sequence is conserved across different species including mouse and human, and since we have observed VIPR antagonists stimulate proliferation of human T cells, there is an increased potential for clinical translation of VIPR antagonists in the treatment of human PDAC.
Citation Format: Sruthi Ravindranathan, Brandon Ware, Mohammad Zaidi, Jingru Zhu, Rohan K. Dhamsania, Shuhua Wang, Yiwen Li, Ishani H. Rao, Susan N. Thomas, Gregory B. Lesinski, Bassel El-Rayes, Edmund K. Waller. Turning up the heat on pancreatic ductal adenocarcinoma via inhibiting vasoactive intestinal peptide signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5571.