HMGA2 Expression in Pancreatic Ductal Adenocarcinoma Controls Tumor Microenvironment and Immunosuppression via IL1α
Yamamoto, N.; Dobersch, S.; Robertson, T. M.; Sim, J. H.; Wallace-Povirk, A.; Chew, N.; Orellana, A. E.; Aggrey-Fynn, J.; Boila, L.; Schutter, A.; Loveless, I. M.; Jang, G. H.; Avanessian, S.; Beatty, G. L.; Hingorani, S. R.; Rydberg Millrud, C.; Steele, N. G.; Barbosa Vendramini Costa, D.; Francescone, R.; Crawford, H. C.; Notta, F.; Barry, K.; Kugel, S.
Show abstract
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 (IL1) promoter and upregulates transcription, increasing IL1 in the TME, in turn inducing immunosuppressive fibroblast polarization, increasing regulatory T cells, and decreasing CD8+ T cells. Blockade of the IL1 signaling axis disrupts this tumor-driven microenvironment phenotype and combines with inhibitors of oncogenic KRAS to improve tumor control.
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