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TGFβ Blocks IFNα/β Release and Tumor Rejection in Spontaneous Mammary Tumors

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, etc.

Nat Commun. 2019 Sep 11;10(1):4131.

PMID: 31511510

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP117570533	DMXAA		117570-53-3	Price

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