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

M. Guerin,F. Régnier,V. Feuillet,L. Vimeux,J. Weiss,G. Bismuth,G. Altan-Bonnet,T. Guilbert,M. Thoreau,V. Finisguerra,E. Donnadieu,A. Trautmann,N. Bercovici

Published 2019 in Nature Communications

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. Interferons have been shown to mediate tumour rejection. Here, in a spontaneous mouse model of breast cancer, the authors show that this is disrupted owing to high levels of TGFβ produced in the tumour.

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