E. M. Dickey1, H. Amirian1, K. Rajkumar1, A. Adams1, S. Singh1, N. Merchant1, A. Bianchi1, J. Datta1 1University Of Miami, Surgery Oncology, Miami, FL, USA
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is associated with dismal prognosis and dense resistance to chemoimmunotherapy. The hallmarks of therapeutic resistance in PDAC are an undruggable genome, stromal desmoplasia and inflammation, and myelo-enriched and T-cell excluded immune microenvironments. The interleukin-1 (IL-1) signaling axis has been implicated as a key driver of these hallmarks. Of IL-1 signaling components, IL1RAP is critical for multivalent IL-1 signal transduction. Therefore, we sought to characterize the clinical and immunologic effects associated with IL1RAP overexpression in human PDAC.
Methods: The Cancer Genome Atlas (TCGA; n=179), Genotype-Tissue Expression (GTEx; n=171), and COMPASS trial (n=168) molecularly annotated databases were queried for IL1RAP gene/pathway expression and its association with disease-free survival (DFS), overall survival (OS), and RECIST objective response after chemotherapy. Single-cell RNA sequencing (scRNAseq) data from human PDAC samples (n=16) was interrogated for cell-specific IL1RAP expression. TISIDB knowledgebase was queried for association between IL1RAP expression and computationally inferred immune metrics.
Results: IL1RAP was strongly overexpressed in TCGA PDAC compared to matched GTEx normal pancreas samples (8.3 vs 0.8 transcripts/million; P-adj<0.05). High IL1RAP expression (>median, n=89) was associated with worse DFS (P=0.01) and OS (P=0.03) compared with low expression (<median, n=89) in TCGA samples. Multiple IL1RAP-encompassing signaling pathways were enriched in transcriptomes of PDAC samples demonstrating progressive disease (i.e., chemoresistance) to FOLFIRINOX or gemcitabine-based chemotherapy in the COMPASS trial dataset. Via immune subtype classification, IL1RAP overexpression was associated with high intratumor heterogeneity, low Th1:Th2 ratio, and activated stromal abundance/wound healing transcriptomes. Immune deconvolution confirmed relative overabundance of not only Th2 and regulatory T-cell phenotypes but also CXCR2+ neutrophilic myeloid-derived suppressor cells (MDSC) in IL1RAP-high tumors. As such, single-cell RNA sequencing in 16 human PDAC samples revealed the dominant expression of IL1RAP in neutrophil and myeloid subsets. Although IL1RAP overexpression was inversely correlated with activated/effector CD4+ and CD8+ T-cell abundance, we observed paradoxical enrichment of B2M, TAP1, and TAP2 genes typically expressed in antigen-presenting myeloid cells as well as immunostimulatory ligand-receptor interactomes in IL1RAP-high PDAC samples.
Conclusion: IL1RAP is associated with chemoresistance and poor outcomes in PDAC, instigating a predominantly tolerogenic immune microenvironment but with intermixed immunogenic elements. IL1RAP may be an attractive target to uncouple myeloid immunosuppression from adaptive antitumor immunity and overcome chemoimmunotherapy resistance in PDAC.