Abstract B016: MHC-II expressing pancreatic tumor cells alter macrophage polarization through VEGFA-NRP1 signaling

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by an immunosuppressive tumor microenvironment (TME) that limits the efficacy of immunotherapies. Tumor-associated macrophages (TAMs) represent a major cellular component of the TME and play a critical role in sustaining immunosuppressive signaling within the tumor. We aim to define the molecular mechanisms and signaling directionality between TAMs and tumor cells to test whether disrupting these pathways can reprogram TAMs to support antitumor immunity. To assess the impact of tumor-intrinsic inflammatory programs on TAM behavior, 9 patient-derived PDAC organoid (PDO) models were analyzed. PDOs were generated from surgical specimens by mechanical and enzymatic dissociation to isolate tumor epithelial cells. Spatial proteomic profiling of 15 PDAC patient samples was performed using imaging mass cytometry to identify proximal cellular populations. In addition, single-cell RNA-sequencing data from 172 human PDAC tumors were analyzed using DominoSignal to infer intercellular crosstalk. This comparison aimed to define how inducible MHC class II (MHC-II) expression on tumor cells shapes TAM phenotypes and to identify the ligand–receptor interactions that govern TAM–tumor communication. PDO cultures stimulated with IFN-γ exhibited robust induction of MHC-II, indicating an inflammatory, antigen-presenting tumor cell state. Spatial profiling of human PDAC tissues demonstrated that MHC-II expressing tumor cells localize closer to macrophages than MHC-II negative tumor cells, suggesting tumor - TAM crosstalk. Single cell transcriptomic analysis identified heterogeneous TAM subsets and demonstrated that MHC-II expressing tumor cells exhibited increased outgoing signaling toward all TAM populations. Among these interactions, VEGFA was downregulated in MHC-II expressing tumor cells, with its receptor NRP1 being enriched on TAMs, implicating this axis in maintenance of an anti-inflammatory TAM phenotype. These findings suggest VEGFA–NRP1 signaling drives immune evasion in PDAC and identifies a therapeutic axis for reprogramming TAMs, providing a foundation for future combination immunotherapy strategies. Tamara Lopez-Vidal, Jacob Mitchell, Kylie Belanger, Richard A. Burkhart, Elana J. Fertig, Won Jin Ho, Jacquelyn W. Zimmerman. MHC-II expressing pancreatic tumor cells alter macrophage polarization through VEGFA-NRP1 signaling [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B016.