Abstract 1205: Targeting vasoactive intestinal peptide signaling to enhance pancreatic cancer responsiveness to immunotherapy
Authors: Ravindranathan Sruthi , Li Yiwen , Wang Shuhua , Zaidi Mohammad Y. , Lesinski Gregory B. , El-Rayes Bassel , Waller Edmund K. 
Published: August 2019

Background: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer related death in the U.S., outranking breast and colorectal cancer by 2030. Being completely refractory to checkpoint therapies, management of PDAC remains an unmet clinical need. Intriguingly, the cancer genome atlas shows elevated mRNA expression of vasoactive intestinal peptide (VIP), a neurotransmitter in exocrine pancreatic cancers. Interestingly, VIP also has immunosuppressive properties leading to decreased T cell proliferation and enhances expansion of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Thus, we are investigating the role of VIP in PDAC progression and the effect of inhibiting VIP signaling for improved responsiveness to immunotherapy.

Methods: Level of secreted VIP in 1) serum of healthy volunteers, 2) untreated PDAC patients, 3) cell culture supernatant from murine melanoma, breast and PDAC cells and 4) serum from mice bearing these cell lines were tested via VIP specific enzyme immunoassay. Effect of inhibiting VIP signaling in-vivo was tested using VIPhyb, an antagonist for VIP receptor. Mice were subcutaneously inoculated with MT5 or luciferase transfected KPC (KPC luc), PDAC cell lines and treated with VIPhyb and/or anti-PD1 treatment after the tumors were palpable. The treatment regimen involved administering 10µg VIPhyb subcutaneously, every day and 200µg anti-PD1 or IgG2a, intraperitoneally, every three days, for 10 days. The tumors were measured using calipers or imaged via IVIS imaging system. The mice were sacrificed when tumors ulcerated or when they reached IACUC endpoint. Immunohistochemistry was performed on tumor tissue sections harvested at the time of sacrifice for expression of VIP, CD8 and DAPI.

Results: Consistent with the human genome atlas, cell culture supernatants collected from murine PDAC cell lines had significantly higher levels of VIP as compared to melanoma and breast cancer cells. Similarly, elevated levels of VIP were observed in mice bearing PDAC tumors, and in plasma from untreated human PDAC patients, when compared to naïve mice and healthy volunteer samples, respectively. Treatment of immune competent mice bearing MT5 or KPC luc PDAC cells with the combination of VIPhyb and anti-PD1 produced complete and durable regression of tumors in 20% of the mice and delayed tumor progression in both tumor models. Further, upon analysis of the tumor tissues sections, significant infiltration of CD8+ T cells was observed in mice treated with the combination of VIPhyb and anti-PD1.

Conclusion: VIP is a novel immune checkpoint pathway in PDAC. Blocking VIP signaling during anti-PD1 therapy, shows improved survival and delayed tumor progression in mouse models of PDAC. Experiments are underway to understand the mechanism of action, as well as, improving the potency of VIPhyb for enhanced clinical outcome.

Citation Format: Sruthi Ravindranathan, Yiwen Li, Shuhua Wang, Mohammad Y. Zaidi, Gregory B. Lesinski, Bassel El-Rayes, Edmund K. Waller. Targeting vasoactive intestinal peptide signaling to enhance pancreatic cancer responsiveness to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1205.