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TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors

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  • Marion V. Guerin

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Fabienne Regnier

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Vincent Feuillet

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Lene Vimeux

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Julia M. Weiss

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014
    University Medical Center)

  • Georges Bismuth

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Gregoire Altan-Bonnet

    (National Cancer Institute)

  • Thomas Guilbert

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Maxime Thoreau

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Veronica Finisguerra

    (Ludwig Institute for Cancer Research, de Duve Institute, Université catholique de Louvain)

  • Emmanuel Donnadieu

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Alain Trautmann

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

  • Nadège Bercovici

    (Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, F-75014)

Abstract

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce strong production of IFNα/β and rejection of transplanted primary tumors. In the present study, we address whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFNα/β production. Mechanistically, we identify TGFβ, which is abundant in spontaneous tumors, as a key molecule limiting this IFN-induced tumor regression by DMXAA. Finally, blocking TGFβ restores the production of IFNα by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGFβ.

Suggested Citation

  • Marion V. Guerin & Fabienne Regnier & Vincent Feuillet & Lene Vimeux & Julia M. Weiss & Georges Bismuth & Gregoire Altan-Bonnet & Thomas Guilbert & Maxime Thoreau & Veronica Finisguerra & Emmanuel Don, 2019. "TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11998-w
    DOI: 10.1038/s41467-019-11998-w
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