Targeting vasoactive intestinal peptide-mediated signaling enhances response to immune checkpoint therapy in pancreatic ductal adenocarcinoma

Sruthi Ravindranathan (), Tenzin Passang, Jian-Ming Li, Shuhua Wang, Rohan Dhamsania, Michael Brandon Ware, Mohammad Y. Zaidi, Jingru Zhu, Maria Cardenas, Yuan Liu, Sanjeev Gumber, Brian Robinson, Anish Sen-Majumdar, Hanwen Zhang, Shanmuganathan Chandrakasan, Haydn Kissick, Alan B. Frey, Susan N. Thomas, Bassel F. El-Rayes, Gregory B. Lesinski and Edmund K. Waller ()
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Sruthi Ravindranathan: Emory University School of Medicine
Tenzin Passang: Emory University School of Medicine
Jian-Ming Li: Emory University School of Medicine
Shuhua Wang: Emory University School of Medicine
Rohan Dhamsania: Emory University School of Medicine
Michael Brandon Ware: Emory University School of Medicine
Mohammad Y. Zaidi: Emory University School of Medicine
Jingru Zhu: Emory University School of Medicine
Maria Cardenas: Emory University School of Medicine
Yuan Liu: Emory University
Sanjeev Gumber: Emory University School of Medicine
Brian Robinson: Emory University School of Medicine
Anish Sen-Majumdar: Cambium Oncology LLC
Hanwen Zhang: Emory University School of Medicine
Shanmuganathan Chandrakasan: Emory University
Haydn Kissick: Emory University
Alan B. Frey: Cambium Oncology LLC
Susan N. Thomas: Georgia Institute of Technology
Bassel F. El-Rayes: Emory University School of Medicine
Gregory B. Lesinski: Emory University School of Medicine
Edmund K. Waller: Emory University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract A paucity of effector T cells within tumors renders pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint therapies. While several under-development approaches target immune-suppressive cells in the tumor microenvironment, there is less focus on improving T cell function. Here we show that inhibiting vasoactive intestinal peptide receptor (VIP-R) signaling enhances anti-tumor immunity in murine PDAC models. In silico data mining and immunohistochemistry analysis of primary tumors indicate overexpression of the neuropeptide vasoactive intestinal peptide (VIP) in human PDAC tumors. Elevated VIP levels are also present in PDAC patient plasma and supernatants of cultured PDAC cells. Furthermore, T cells up-regulate VIP receptors after activation, identifying the VIP signaling pathway as a potential target to enhance T cell function. In mouse PDAC models, VIP-R antagonist peptides synergize with anti-PD-1 antibody treatment in improving T cell recruitment into the tumors, activation of tumor-antigen-specific T cells, and inhibition of T cell exhaustion. In contrast to the limited single-agent activity of anti-PD1 antibodies or VIP-R antagonist peptides, combining both therapies eliminate tumors in up to 40% of animals. Furthermore, tumor-free mice resist tumor re-challenge, indicating anti-cancer immunological memory generation. VIP-R signaling thus represents a tumor-protective immune-modulatory pathway that is targetable in PDAC.

Date: 2022
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DOI: 10.1038/s41467-022-34242-4

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