Targeting androgen-driven resistance to immune checkpoint inhibitors in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited therapeutic options and striking sex-based differences in immune responses. Despite the transformative impact of immune checkpoint inhibitors (ICI) in oncology, their efficacy in PDAC is notably poor. Our research reveals that the vasoactive intestinal polypeptide (VIP) receptor (VPAC) acts as a novel immune checkpoint that suppresses macrophage phagocytosis and adaptive anti-tumor immunity. Notably, VPAC blockade enhances macrophage-mediated tumor control in female PDAC models, but not in males. Whereas androgen signaling suppresses macrophage-mediated immunity in males. Androgen receptor blockade overcomes this and sensitizes VPAC antagonist response in male PDAC models. Building on these insights, we propose a sex- specific approach to reinvigorate the PDAC immune microenvironment by targeting VIP receptor 1 (VPAC1) in females and combining androgen receptor (AR) inhibition with VPAC blockade in males. Thus, our central hypothesis is that activating macrophage phagocytosis by targeting immune checkpoints or androgen receptor (AR) promotes an immune-permissive TME, enhances ICI responses and suppresses PDAC progression. We aim to: Aim 1: Define the sex-specific differences in macrophages regulating anti-tumor immunity against PDAC. We will elucidate how VPAC1 in females and AR/VPAC1 cooperation in males contribute to PDAC immune evasion. By leveraging multiplex fluorescence microscopy, single-cell RNA sequencing (scRNAseq), and functional assays, we will characterize macrophage-T cell interactions and assess the impact of VPAC1 and AR inhibition on tumor immunity. Aim 2: Enhance anti-tumor immune responses by combining VPAC blockade with macrophage- checkpoint inhibitors. We will evaluate the therapeutic potential of combining VPAC1/PD-1 blockade with TIM3 inhibition to amplify macrophage-mediated anti-tumor immunity in both sexes. Our murine PDAC models and mechanistic studies will determine the efficacy and underlying mechanisms of this approach. This project is highly innovative, introducing VPAC1 as a novel macrophage phagocytosis checkpoint and defining its role in sex-specific immunosuppression. Our strategy holds significant translational potential to inform precision immunotherapy and advance clinical interventions for PDAC patients. By addressing the profound sex disparities in immune response, our findings could reshape immunotherapeutic paradigms and improve survival outcomes for both male and female PDAC patients. Project Number: 1R21CA307819-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Edmund Waller (+1 co-PI) | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $402,401 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CDPT-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11284932