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

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.

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

“…Fig.S3E and F ), suggesting VPAC2 signaling may interact with interferon-gamma receptor signaling to enhance immunogenicity in the TME. We previously published that blockade of VIP-receptors using ANT308, a high-affinity VIP-receptor antagonist, enhanced T cell activation and anti-cancer immunity in PDAC (9). Findings from our current study suggest that our previous report showing the anti-cancer activity of the VIP-receptor antagonist in PDAC models could be attributed partially to tumor-cell autonomous and non-tumor-cell autonomous effects from VPAC2 signaling in PDAC cells as defined in this paper.…”

“…Total RNA was isolated using RNeasy Plus Micro Kit (Qiagen), and first-strand cDNA was prepared using an AMV RNA PCR kit (TaKaRa) from 1 mg of total RNA. PCR amplification for VPAC2 mRNA detection was carried out as previously described (9). For qPCR, PowerUp™ SYBR™ Green Master Mix was used.…”

“…PDAC has a highly desmoplastic and immunosuppressive tumor microenvironment (TME) with a paucity of effector T cells that limits the effectiveness of anti-CTLA-4 and anti-PD1 monotherapies (6)(7)(8), further emphasizing the need to understand the biological underpinnings of PDAC that lead to immune resistance. Our group previously showed that PDAC overexpression of vasoactive intestinal polypeptide (VIP) enables cancers to evade immune surveillance (9).…”

“…In addition to its previously known functions, growing research indicates that VIP has anti-inflammatory effects on T cells, macrophages, and plasmacytoid dendritic cells (13–17). Our published data demonstrate that VIP expression by pancreatic cancer cells leads to paracrine signaling on T cells via VIP receptors, resulting in T cell suppression and resistance to anti-PD-1 therapy (9). We observed that pancreatic cancer cells also express VPAC1 and VPAC2 and that absence of VPAC2 on cancer cells results in delayed tumor growth rate in vivo , suggesting a potential autocrine function of VIP via VPAC2 (9).…”

Pressure-Dependent Elevation of Vasoactive Intestinal Peptide Level in Chicken Choroid

“…Overall, VIP is known to be a potent neurotransmitter further involved in the regulation of circadian rhythms [ 71 ], hormones [ 72 , 73 ], the intestines [ 74 , 75 ] and cancer [ 76 , 77 , 78 ]. As these GPCRs were observed in different immune cells (e.g., macrophages, CD4+ T cells and CD8+ T cells lymphocytes) [ 79 , 80 , 81 ], an involvement in the immune response can be assumed.…”