HMGA2 Expression in Pancreatic Ductal Adenocarcinoma Controls Tumor Microenvironment and Immunosuppression via IL1α
Year: 2026
Type: preprint
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 (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. Statement of Significance 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.
Authors: Naomi Yamamoto, Stephanie Dobersch, Tess M. Robertson, Jae Hyung Sim, Adrianne Wallace-Povirk, Nayvin W. Chew, Alexander E. Orellana, Joana Aggrey-Fynn, Liberalis Debraj Boila, Aidan Schutter, Ian M. Loveless, Gun Ho Jang, Shayan Avanessian, Gregory L. Beatty, Sunil R. Hingorani, Camilla Rydberg Millrud, Nina G. Steele, Debora Barbosa Vendramini-Costa, Ralph Francescone, Howard C. Crawford, Faiyaz Notta, Kevin C. Barry, Sita Kugel
Institutions: University of Washington, Fred Hutch Cancer Center, Michigan State University, Henry Ford Health, Ontario Institute for Cancer Research, Abramson Cancer Center, University of Pennsylvania, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, University of Cincinnati, Wayne State University, University Health Network, University of Toronto, Princess Margaret Cancer Centre
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7220696206