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

Marion V. Guerin, Fabienne Regnier, Vincent Feuillet, Lene Vimeux, Julia M. Weiss, Georges Bismuth, Gregoire Altan-Bonnet, Thomas Guilbert, Maxime Thoreau, Veronica Finisguerra, Emmanuel Donnadieu, Alain Trautmann and Nadège Bercovici ()
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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
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

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11998-w

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