Abstract B011: HMGA2 controls fibroblast skewing and immune infiltration in basal pancreatic cancer

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. Recent efforts to understand the tumor microenvironment (TME) of PDAC have extensively characterized both immune and stromal compartments. In previous work, we have shown that HMGA2+ basal-like pancreatic tumors are associated with higher fibroblastic activation and lower CD8+ T cell infiltrate than HMGA2- classical tumors. To mechanistically determine how HMGA2 expression alters the TME, we implemented three independent data sets; single-cell, microdissected and bulk RNA sequencing and found that HMGA2+ cancer cells also had high expression of ILA. 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, displaces histone linker H1 and upregulates transcription, increasing IL1α in the TME. In vivo, a genetically engineered mouse model with high levels of tumoral HMGA2 also displayed high IL6+ LRRC15+ fibroblast content and low CD8+ T cell content in tumors compared to HMGA2low littermates. We then orthotopically implanted murine KrasLSL-G12D/+, Trp53L/+, Pdx1-Cre, Rosa26YFP/YFP (KPCY) engineered to overexpress HMGA2 (oeHMGA2) or empty vector. oeHMGA2 accelerated disease course, increased metastases, and was sufficient to remodel the TME, including lower CD8+ T cell, and higher NK cell, and Treg populations. These TME changes were all prevented when oeHMGA2 cells were implanted into IL1R1 knock-out mice. Finally, we find that preclinical interruption of the IL1R pathway was sufficient to reverse IL6 and LRRC15 skewing in basal conditioned media-treated human PSCs and naïve murine fibroblasts and in vivo. Blockade of the IL1α signaling axis disrupts this tumor-driven microenvironment phenotype and combines with inhibitors of oncogenic KRAS to improve tumor control. These data demonstrate the role of tumoral HMGA2 expression in controlling an immunosuppressive TME, highlight a potential biomarker to determine TME phenotype in PDAC patients and introduce a novel subtype-specific immunomodulatory therapy.