Inflammation and chemotherapy induce immune mimicry in PDAC and promote crosstalk between fibroblasts and tumor cells

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality partly due to refractory responses to chemotherapeutics. Factors secreted by immune cells and cancer-associated fibroblasts (CAFs) like interleukin (IL)-6 family members can activate Signal transducer and activator of transcription 3 (STAT3) in PDAC cells, driving drug resistance. We developed a STAT3 effector gene signature induced by inflammatory mediators that strongly correlates with poor relapse-free survival in PDAC. One of the signature genes, IL7R , encoding interleukin-7 receptor alpha (IL7Ralpha), is commonly associated with lymphoid cells. Importantly, we observed IL7R enrichment in tumor cells from chemotherapy-treated patients compared to treatment-naïve patients that correlates with an increased epithelial-to-mesenchymal transition (EMT) score. Furthermore, we identified high expression of the IL7Ralpha ligand thymic stromal lymphopoietin (TSLP) primarily restricted to CAFs from PDAC patients. PDAC cells exposed to an IL-6 family member gained IL7Ralpha expression leading to hyperactivation of the tumor-promoting transcription factors, STAT1, STAT3, and STAT5 in response to TSLP. We contend that IL7R expression represents an “immune mimicry” response leveraged by tumor cells to gain stress tolerance, drug resistance, and EMT through crosstalk with CAFs, leading to an aggressive cancer phenotype.