VPAC2 receptor signaling promotes pancreatic cancer cell growth and decreases the immunogenicity of the tumor microenvironment.

Passang, T.; Wang, S.; Zhang, H.; Zeng, F.; Hsu, P.-C.; Wang, W.; Li, J. M.; Liu, Y.; Ravindranathan, S.; Lesinski, G. B.; Waller, E. K.

doi:10.1101/2024.01.16.575872

bioRxiv · 10.1101/2024.01.16.575872

VPAC2 receptor signaling promotes pancreatic cancer cell growth and decreases the immunogenicity of the tumor microenvironment.

Passang, T.·Wang, S.·Zhang, H.·Zeng, F.·Hsu, P.-C.·Wang, W.·Li, J. M.·Liu, Y.·Ravindranathan, S.·Lesinski, G. B.·Waller, E. K.

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Abstract

Identifying mechanisms underlying tumor growth and immune resistance is needed to treat pancreatic ductal adenocarcinoma (PDAC) effectively. The complexity of the tumor microenvironment (TME) suggests that the crosstalk between cells in the TME could drive drug resistance and relapse in PDAC. We have previously determined that vasoactive intestinal peptide (VIP) is overexpressed in PDAC and that VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to anti-PD1 therapy. In this study, we show that pancreatic cancer cells engage in autocrine signaling of VIP through VIP-receptor 2 (VPAC2), and that high co-expression of VIP with VPAC2 leads to reduced relapse-free survival in PDAC patients. Mechanistically, we identified piwi-like RNA-mediated gene silencing2 (Piwil2) as a tumor-cell intrinsic protein downstream of VPAC2 that regulates cancer cell growth. In addition, we discovered TGF{beta}-1 as a potential tumor-extrinsic inhibitor of T cell function induced by VPAC2 signaling. In vivo, knock out and knockdown of VPAC2 on PDAC cells led to reduced tumor growth rate and increased sensitivity to anti-PD-1 therapy in various mouse models of PDAC that were T-cell dependent. Overall, these findings emphasize the implications of VIP/VPAC2 signaling in the PDAC tumor microenvironment and further support the rationale for developing VPAC2-specific antagonists. SignificanceThe autocrine VIP signaling via VPAC2 promotes cancer cell growth and dampens T cell function in pancreatic ductal adenocarcinoma and thus represents a potential therapeutic target in PDAC.

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Passang, T., Wang, S., Zhang, H., Zeng, F., Hsu, P.-C., Wang, W., Li, J. M., Liu, Y., Ravindranathan, S., Lesinski, G. B., Waller, E. K.. 2024-01-17. VPAC2 receptor signaling promotes pancreatic cancer cell growth and decreases the immunogenicity of the tumor microenvironment.. https://doi.org/10.1101/2024.01.16.575872

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