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BP21. Myeloid-Stromal IL1RAP as a Therapeutic Vulnerability in Pancreatic Cancer: Rationale for a Neoadjuvant Chemoimmunotherapy Clinical Trial

Friday, March 6, 2026
1:58 PM - 2:05 PM MST
Location: 301A
Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to chemo- and immuno-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). 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 IL1RAP expression. Post hoc analysis of CANFOUR trial (NCT03267316), in which advanced PDAC patients were treated with the anti-IL1RAP antibody nadunolimab (Nadu) and gemcitabine+nab-paclitaxel (GnP), was performed. Preclinical studies, including scRNAseq and flow cytometry were conducted in IL1RAPhi Ptf1aCre/+;LSL-KrasG12D;Tgfbr2fl/fl (PKT) mice treated with murine nadunolimab (mNadu). Combination mNadu, GnP, and anti-PD1 therapy was tested in survival studies.


Results: In HTAN, 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 with Nadu+GnP treatment. In PKT mice, mNadu reduced tumor volume (p=0.019) and stromal fibrosis. Flow cytometry showed reduced myeloid cell (p=0.008) and increased T-cell (p=0.003) abundance, which were corroborated in paired human biopsies pre/post Nadu treatment, showing diminished myeloid cell infiltration and expansion of T-cells. scRNAseq in PKT tumors revealed reprogramming in myeloid (↑antigen presentation, Type I IFN response; ↓IL-1/TNF signaling) and T-cell (↑activation/memory, TCR engagement; ↓regulatory/exhausted states) transcriptomes. Phenotypic skewing toward memory progenitor memory CD8+ subsets (Ly108+CD69+/-) supported enhanced immune responsiveness. Triple therapy (mNadu+GnP+anti-PD1) significantly prolonged survival vs 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 pools and improve chemoimmunotherapy sensitivity. These findings support an upcoming neoadjuvant trial combining Nadu with GnP/anti-PD1 in patients with operable PDAC.

Learning Objectives:

  • ILRAP expression was enriched in samples from patients with chemotherapy resistance, predominantly in the myeloid and stromal compartments.
  • Chemoimmunotherapy sensitivity in pancreatic ductal adenocarcinoma could be enhanced by disrupting myeloid stromal networks within the tumor microenvironment by IL1RAP inhibition.