Summary
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.
Footnotes
Lead contact: nadege.bercovici{at}inserm.fr; Phone +33680527946; Fax +33140516555; Institut Cochin, 22 rue Méchain, 75014 Paris
Abbreviations: DMXAA: 5,6-dimethylxanthenone-4-acetic acid; IFN: interferon; IRF3: Interferon regulatory factor 3; IRF7: Interferon regulatory factor 7; MHCII: Major histocompatibility complex II; MMTV: Mouse mammary tumor virus; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PyMT: polyomavirus middle T antigen; STING: Stimulator of interferon genes; TAM: tumor-associated macrophages; TBK1: TANK-binding kinase 1; TGFβ: tumor growth factor beta; TNFα: Tumor necrosis factor alpha.