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

• Published in: Nature communications Vol. 10; no. 1; pp. 4131 - 12
• Main Authors: Guerin, Marion V., Regnier, Fabienne, Feuillet, Vincent, Vimeux, Lene, Weiss, Julia M., Bismuth, Georges, Altan-Bonnet, Gregoire, Guilbert, Thomas, Thoreau, Maxime, Finisguerra, Veronica, Donnadieu, Emmanuel, Trautmann, Alain, Bercovici, Nadège
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14/19; 14/63; 631/250; 631/67; 64/110; 96/21; 96/95; Acetic acid; Animals; Anticancer properties; Breast cancer; Cell activation; Female; Humanities and Social Sciences; Interferon; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - metabolism; Interferon-alpha - metabolism; Interferon-beta - metabolism; Life Sciences; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Mammary Neoplasms, Animal - metabolism; Mammary Tumor Virus, Mouse - metabolism; Mice; multidisciplinary; Phosphorylation; Phosphorylation - drug effects; Regression; Rejection; Science; Science (multidisciplinary); Stimulators; Transforming Growth Factor beta - metabolism; Tumors; Xanthones - pharmacology; α-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11998-w

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.