TY - JOUR T1 - TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors JF - bioRxiv DO - 10.1101/336990 SP - 336990 AU - Marion V. Guerin AU - Fabienne Regnier AU - Vincent Feuillet AU - Lene Vimeux AU - Julia M. Weiss AU - Georges Bismuth AU - Gregoire Altan-Bonnet AU - Thomas Guilbert AU - Maxime Thoreau AU - Veronica Finisguerra AU - Emmanuel Donnadieu AU - Alain Trautmann AU - Nadège Bercovici Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/07/09/336990.abstract N2 - Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA can induce a strong production of IFNα/β and the rejection of transplanted primary tumors. In the present study, we addressed 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 identified TGFβ 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. ER -