HMGA2 Expression in Pancreatic Ductal Adenocarcinoma Controls Tumor Microenvironment and Immunosuppression via IL1α

The basal-like subtype of pancreatic ductal adenocarcinoma (PDAC) is associated with poor outcomes and increased chemoresistance. Expression of high mobility group AT-hook 2 (HMGA2), a chromatin architectural protein, marks basal PDAC cells and associates with specific features of the tumor microenvironment (TME), including more immunosuppressive cancer associated fibroblasts (CAFs) and fewer cytotoxic CD8 ⁺ T cells. Expression of HMGA2 by tumor cells leads to upregulation of the immunosuppressive markers interleukin 6 (IL6) and leucine-rich repeat containing protein 15 (LRRC15) in associated fibroblasts. Mechanistically, HMGA2 in the tumor cell binds the interleukin 1 alpha (IL1α) promoter and upregulates transcription, increasing IL1α in the TME, in turn inducing immunosuppressive fibroblast polarization, increasing regulatory T cells, and decreasing CD8 ⁺ T cells. Blockade of the IL1α signaling axis disrupts this tumor-driven microenvironment phenotype and combines with inhibitors of oncogenic KRAS to improve tumor control.

The tumor microenvironment of pancreatic ductal adenocarcinoma drives immunosuppression, but causal relationships between PDAC subtypes and the TME have not been established. We report direct regulation of IL1α signaling by a basal PDAC-specific factor that controls fibroblast polarization and drives immunosuppression.