TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors
| Autor: | Emmanuel Donnadieu, Thomas Guilbert, Vincent Feuillet, Fabienne Regnier, Maxime Thoreau, Veronica Finisguerra, Alain Trautmann, Lene Vimeux, Nadège Bercovici, Julia Miriam Weiss, Marion V. Guerin, Gilles Renault |
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| Přispěvatelé: | Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre d'Etudes et Recherches en Thermique, Environnement et Systèmes [Créteil] (CERTES EA 3481), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Center for Cancer Systems Biology, Memorial Sloane Kettering Cancer Center [New York], Service des Recherches Métallurgiques Appliquées (SRMA), Département des Matériaux pour le Nucléaire (DMN), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig Institute for Cancer Research, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), donnadieu, emmanuel |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Xanthones
Science [SDV]Life Sciences [q-bio] Immunology Mammary Neoplasms Animal Article Mice 03 medical and health sciences 0302 clinical medicine Transforming Growth Factor beta TGF beta signaling pathway medicine Animals Phosphorylation lcsh:Science Cancer 030304 developmental biology 0303 health sciences Chemistry Macrophages Interferon-alpha Interferon-beta medicine.disease 3. Good health Blockade [SDV] Life Sciences [q-bio] Sting Mammary Tumor Virus Mouse 030220 oncology & carcinogenesis Stimulator of interferon genes Cancer research Female Interferon Regulatory Factor-3 lcsh:Q IRF3 Infiltration (medical) Transforming growth factor |
| Zdroj: | Nature Communications Nature Communications, 2019, 10 (1), ⟨10.1038/s41467-019-11998-w⟩ Nature Communications, Nature Publishing Group, 2019, 10 (1), ⟨10.1038/s41467-019-11998-w⟩ Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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