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

Guerin, M. V.; Regnier, F.; Feuillet, V.; Vimeux, L.; Weiss, J. M.; Guilbert, T.; Thoreau, M.; Renault, G.; Finisguerra, V.; Donnadieu, E.; Trautmann, A.; Bercovici, N.

doi:10.1101/336990

bioRxiv · 10.1101/336990

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

Guerin, M. V.·Regnier, F.·Feuillet, V.·Vimeux, L.·Weiss, J. M.·Guilbert, T.·Thoreau, M.·Renault, G.·Finisguerra, V.·Donnadieu, E.·Trautmann, A.·Bercovici, N.

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Abstract

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 IFN/{beta} 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 IFN/{beta} production. Mechanistically, we identified TGF{beta} abundant in spontaneous tumors, as a key molecule limiting this IFN-induced-tumor regression by DMXAA. Finally, blocking TGF{beta} restores the production of IFN 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 TGF{beta}.

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Guerin, M. V., Regnier, F., Feuillet, V., Vimeux, L., Weiss, J. M., Guilbert, T., Thoreau, M., Renault, G., Finisguerra, V., Donnadieu, E., Trautmann, A., Bercovici, N.. 2018-06-01. TGFβ blocks STING-induced IFNα/ β release and tumor rejection in spontaneous mammary tumors. https://doi.org/10.1101/336990

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