Myeloid-stromal IL1RAP as a therapeutic vulnerability in pancreatic cancer: Rationale for a neoadjuvant chemoimmunotherapy clinical trial.

745 Background: Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to chemo- and immune-therapy due to a tumor microenvironment (TME) dominated by myeloid-stromal immunosuppressive circuitries and T-cell dysfunction. Key mediators are interleukin-1 (IL-1) family cytokines, which converge on IL-1 receptor accessory protein (IL1RAP) signaling to reinforce a tolerogenic, pro-inflammatory TME. We hypothesized that IL1RAP-expressing myeloid-stromal networks sustain a therapeutic barrier in PDAC, and that disrupting this via IL1RAP inhibition could enhance chemoimmunotherapy efficacy. Methods: PDAC samples from the Human Tumor Atlas Network (HTAN) were stratified by cell-type IL1RAP expression. Clinical outcomes in patients treated with the anti-IL1RAP antibody nadunolimab (CAN04) in Phase II CANFOUR trial (NCT03267316) were stratified by immune and stromal IL1RAP expression; paired pre/post CAN04 biopsies were analyzed by multiplex immunofluorescence. Preclinical studies were conducted in IL1RAP hi Ptf1a Cre/+ ;LSL-KrasG12D;Tgfbr2 fl/fl (PKT) murine model. CAN04-treated tumors were analyzed by scRNAseq, flow cytometry, and histology. Combination CAN04, gemcitabine+nab-paclitaxel (GnP), and anti-PD1 therapy was tested in survival studies. Results: In HTAN, IL1RAP expression was elevated across myeloid, stromal, and tumor TME networks; notably, IL1RAP was enriched in chemotherapy-resistant samples, predominantly in myeloid and stromal transcriptomes. Stratification of specimens from CANFOUR trial revealed correlation between high stromal (p=0.006) and myeloid (p=0.014) IL1RAP expression and prolonged duration of response. In PKT mice, CAN04 reduced tumor volume (p=0.019) and stromal fibrosis. Flow cytometry showed reduced myeloid (p=0.008) and increased T-cell (p=0.003) abundance, which were corroborated in paired pre/post CAN04 human biopsies, showing diminished CD11b + CD14 + /CD15 + myeloid infiltration and expansion of granzymeB + Ki67 + CD8 + T-cells. scRNAseq in PKT tumors revealed reprogramming in myeloid (↑antigen presentation and Type I IFN 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 (CAN04/GnP/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 CAN04 with chemoimmunotherapy in patients with operable PDAC.