ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to chemotherapy and immunotherapy due to a tumor microenvironment (TME) dominated by myeloid-stromal immunosuppressive circuitries and T-cell dysfunction. Key mediators of this chemoimmunoresistance are interleukin-1 (IL-1) family cytokines (IL-1α/β, IL-33, IL-36), which converge on IL-1 receptor accessory protein (IL1RAP) signaling to reinforce a tolerogenic, pro-inflammatory TME. We hypothesized that IL1RAP-expressing myeloid-stromal compartments sustain a therapeutic barrier in PDAC, and that disrupting this via pharmacologic IL1RAP inhibition could reprogram the TME to enhance chemoimmunotherapy efficacy. METHODS: Chemoresistance in PDAC samples from Human Tumor Atlas Network (HTAN) was stratified by cell-type IL1RAP expression. Clinical outcomes in patients treated with anti-IL1RAP Ab nadunolimab (Nadu)+gemcitabine+nab-paclitaxel (GnP) in Phase II CANFOUR trial (NCT03267316) were stratified by immune and stromal IL1RAP expression; paired PDAC biopsies pre-/post-treatment were analyzed by mIF. Preclinical studies were conducted in the IL1RAPhi stromatogenic Ptf1aCre/+;LSL-KrasG12D;Tgfbr2fl/fl (PKT) murine model. Nadu surrogate Ab-treated tumors were analyzed by scRNAseq, flow cytometry, and histology. Combination Nadu, GnP, and anti-PD1 therapy was tested in survival \ studies. RESULTS: In HTAN dataset, IL1RAP expression was elevated across multiple TME compartments—myeloid, cancer-associated fibroblast (CAF), and tumor cells; notably, IL1RAP was selectively enriched in chemotherapy-resistant (vs sensitive) samples, predominantly in myeloid and CAF/stromal transcriptomes. Stratification of evaluable specimens from CANFOUR trial revealed correlation between high stromal/CAF (p=0.0058) and myeloid (p=0.014) IL1RAP expression and prolonged duration of response to Nadu+GnP. In PKT mice, Nadu treatment reduced tumor volume (p=0.019) and stromal fibrosis. Flow cytometry showed reduced trafficking/persistence (p=0.0077) and increased T-cell abundance (p=0.0033), which were corroborated by mIF in paired human PDAC biopsies pre/post Nadu treatment, showing diminished CD11b+CD14+/CD15+ myeloid infiltration and expansion of GzmB+Ki67+CD8+ T-cells. scRNAseq in PKT tumors revealed reprogramming in myeloid (↑antigen presentation and Type IIFN response; ↓IL-1/TNF signaling) and T-cell (↑activation/memory, TCR engagement, IL-2 signatures; ↓regulatory/exhausted states) subsets. Phenotypic skewing toward memory progenitor-exhausted CD8+ subsets (Ly108+CD69+/-) supported enhanced immune responsiveness. Triple therapy with Nadu, GnP, and anti-PD-1 significantly prolonged survival versus controls (p<0.001). CONCLUSIONS: IL1RAP-expressing myeloid-stromal networks may represent a distinct therapeutic barrier in PDAC, which can be disrupted pharmacologically to invigorate immunotherapy-permissive CD8+ T-cell subsets and improve chemoimmunotherapy sensitivity. These findings support an upcoming neoadjuvant trial combining nadunolimab with chemoimmunotherapy in patients with operable PDAC.
