NIH grant: Targeting VIP–VPAC Signaling to Reverse Immune Exclusion and Enhance Immunotherapy Response in Pancreatic Cancer (1R01CA314282-01)

retained text

NIH grant 1R01CA314282-01: Targeting VIP–VPAC Signaling to Reverse Immune Exclusion and Enhance Immunotherapy Response in Pancreatic Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Gregory B. Lesinski. Award: $636358.
Start: 2026-06-18T00:00:00.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that is largely unresponsive to chemotherapy
and current immune checkpoint blockade drugs, highlighting a critical need for the development of innovative
therapeutic strategies. This R01 proposal targets vasoactive intestinal peptide (VIP), an immunosuppressive
neuropeptide overexpressed in PDAC, which signals through VIP receptors (VPAC) on cancer cells, T cells, and
myeloid cells within the tumor microenvironment. Based on our recent success in developing selective and potent
VPAC receptor antagonists, we hypothesize that blocking VPAC signaling will reverse immunosuppression in
the PDAC TME by reducing immune checkpoint expression, enhancing chemokine-driven infiltration of cytotoxic
T cells, and disrupting immunosuppressive interactions between T cells and myeloid cells, ultimately leading to
durable anti-cancer immunity.
We propose three specific aims to explore the immunosuppressive roles of VPAC signaling in PDAC. Aim 1 will
identify the primary sources of VIP in PDAC tumors and characterize the effects of VPAC signaling on immune
cell function and phenotype within the tumor microenvironment. Aim 2 will investigate how VPAC signaling
influences immune cell migration into tumors by modulating chemokine receptors and directional signaling. Aim
3 will determine how VPAC signaling regulates interactions between T cells and immunosuppressive myeloid
cells, particularly tumor-associated macrophages, and the resulting impact on anti-cancer immune responses
and immunological memory.
Our preliminary findings indicate that combined inhibition of VPAC signaling and PD-1 significantly enhances the
regression of PDAC tumors in multiple mouse models, generating lasting protective immunity in cured mice
without triggering autoimmune responses. We will use novel methods to pursue our aims, including inducible
genetically engineered mouse models (GEMM) of PDAC, long-acting VPAC antagonists engineered with
immunoglobulin Fc domains to improve their plasma half-life, and advanced microfluidics technologies to analyze
immune cell movement within tumors. Animal experiments will be used to validate the translational potential of
observations from in vitro organoids and microfluidic experiments. The GEMM and orthotopic mouse models of
PDAC are necessary to provide critical insights into the 3-D structure of the TME and tumor regression in response to our
novel immunotherapy. This research will be conducted by a multidisciplinary team with complementary expertise
that will clarify the therapeutic potential of VPAC signaling inhibition in PDAC using sophisticated experimental
tools and single-cell RNA sequencing. Ultimately, these findings could significantly improve the development of
immunotherapeutic strategies for PDAC, potentially enhancing patient outcomes in pancreatic cancer and other
malignancies expressing high VIP levels.

document fetched 2026-06-28 13:47