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Article Dans Une Revue Nature Communications Année : 2019

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

Résumé

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 + tumorassociated 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.
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Dates et versions

hal-02404270 , version 1 (21-12-2020)

Identifiants

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Marion Guérin, Fabienne Regnier, Vincent Feuillet, Lene Vimeux, Julia Weiss, et al.. TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors. Nature Communications, 2019, 10 (1), ⟨10.1038/s41467-019-11998-w⟩. ⟨hal-02404270⟩
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