Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity

Deyong Jia, Zhicheng Zhou, Oh-Joon Kwon, Li Zhang, Xing Wei, Yiqun Zhang, Mingyang Yi, Martine P. Roudier, Mary C. Regier, Ruth Dumpit, Peter S. Nelson, Mark Headley, Lawrence True, Daniel W. Lin, Colm Morrissey, Chad J. Creighton and Li Xin ()
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Deyong Jia: University of Washington
Zhicheng Zhou: University of Washington
Oh-Joon Kwon: University of Washington
Li Zhang: University of Washington
Xing Wei: University of Washington
Yiqun Zhang: Baylor College of Medicine
Mingyang Yi: University of Washington
Martine P. Roudier: University of Washington
Mary C. Regier: University of Washington
Ruth Dumpit: Fred Hutchinson Cancer Research Center
Peter S. Nelson: Fred Hutchinson Cancer Research Center
Mark Headley: Fred Hutchinson Cancer Research Center
Lawrence True: University of Washington
Daniel W. Lin: University of Washington
Colm Morrissey: University of Washington
Chad J. Creighton: Baylor College of Medicine
Li Xin: University of Washington

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Cancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity. Increasing prostatic stromal Foxf2 sensitizes prostate cancer to the immune checkpoint blockade therapies. Augmenting lung stromal Foxf2 also mediates an immunosuppressive milieu and inhibits lung colonization of prostate cancer. FOXF2 is expressed higher in the stroma of human transition zone (TZ) than peripheral zone (PZ) prostate. The stromal FOXF2 expression level in primary prostate cancers inversely correlates with the Gleason grade. Our study establishes Foxf2 as a stromal transcription factor modulating the tumor immune microenvironment and potentially explains why cancers are relatively rare and indolent in the TZ prostate.

Date: 2022
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DOI: 10.1038/s41467-022-34665-z

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