Abstract 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 (IL7Rα), 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 IL7Rα ligand thymic stromal lymphopoietin (TSLP) primarily restricted to CAFs from PDAC patients. PDAC cells exposed to an IL-6 family member gained IL7Rα 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. Citation Format: Carson Cable, Qinlin Jiang, Kourosh Kouhmareh, Richard L. Klemke, Ryan Matthew Shepard, Alejandro D. Campos, Sara M. Weis, David A. Cheresh. Inflammation and chemotherapy induce immune mimicry in PDAC and promote crosstalk between fibroblasts and tumor cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7446.
Cable et al. (Fri,) studied this question.