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STAT3 in tumor fibroblasts promotes an immunosuppressive microenvironment in pancreatic cancer. Life Sci Alliance 2022 Nov;5(11)



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Pubmed Central ID




Scopus ID

2-s2.0-85134426331 (requires institutional sign-in at Scopus site)   11 Citations


Pancreatic ductal adenocarcinoma (PDAC) is associated with an incredibly dense stroma, which contributes to its recalcitrance to therapy. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types within the PDAC stroma and have context-dependent regulation of tumor progression in the tumor microenvironment (TME). Therefore, understanding tumor-promoting pathways in CAFs is essential for developing better stromal targeting therapies. Here, we show that disruption of the STAT3 signaling axis via genetic ablation of Stat3 in stromal fibroblasts in a Kras G12D PDAC mouse model not only slows tumor progression and increases survival, but re-shapes the characteristic immune-suppressive TME by decreasing M2 macrophages (F480+CD206+) and increasing CD8+ T cells. Mechanistically, we show that loss of the tumor suppressor PTEN in pancreatic CAFs leads to an increase in STAT3 phosphorylation. In addition, increased STAT3 phosphorylation in pancreatic CAFs promotes secretion of CXCL1. Inhibition of CXCL1 signaling inhibits M2 polarization in vitro. The results provide a potential mechanism by which CAFs promote an immune-suppressive TME and promote tumor progression in a spontaneous model of PDAC.

Author List

Lefler JE, MarElia-Bennett CB, Thies KA, Hildreth BE 3rd, Sharma SM, Pitarresi JR, Han L, Everett C, Koivisto C, Cuitino MC, Timmers CD, O'Quinn E, Parrish M, Romeo MJ, Linke AJ, Hobbs GA, Leone G, Guttridge DC, Zimmers TA, Lesinski GB, Ostrowski MC


Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

CD8-Positive T-Lymphocytes
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Pancreatic Neoplasms
Tumor Microenvironment