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TGFß receptor inhibition unleashes interferon-ß production by tumor-associated macrophages and enhances radiotherapy efficacy.
Hamon, Pauline; Gerbé De Thoré, Marine; Classe, Marion; Signolle, Nicolas; Liu, Winchygn; Bawa, Olivia; Meziani, Lydia; Clémenson, Céline; Milliat, Fabien; Deutsch, Eric; Mondini, Michele.
Affiliation
  • Hamon P; INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • Gerbé De Thoré M; INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • Classe M; INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • Signolle N; Départment de Pathologie, Gustave Roussy, Villejuif, France.
  • Liu W; Plateforme de pathologie expérimentale et translationnelle, UMS AMMICA, Gustave Roussy, Villejuif, France.
  • Bawa O; INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • Meziani L; Départment de Pathologie, Gustave Roussy, Villejuif, France.
  • Clémenson C; INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • Milliat F; INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • Deutsch E; Department of RAdiobiology and Regenerative MEDicine (SERAMED), Laboratory of MEDical Radiobiology (LRMed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France.
  • Mondini M; INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France michele.mondini@gustaveroussy.fr eric.deutsch@gustaveroussy.fr.
J Immunother Cancer ; 10(3)2022 03.
Article in En | MEDLINE | ID: mdl-35301235
BACKGROUND: Transforming growth factor-beta (TGFß) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGFß with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGFß participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations. METHODS: We used the clinically relevant TGFß receptor 2 (TGFßR2)-neutralizing antibody MT1 and the small molecule TGFßR1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer. RESULTS: We demonstrated that TGFß pathway inhibition strongly increased the efficacy of RT. TGFßR2 antibody upregulated interferon beta expression in tumor-associated macrophages within the irradiated tumors and favored T cell infiltration at the periphery and within the core of the tumor lesions. We highlighted that both the antitumor efficacy and the increased lymphocyte infiltration observed with the combination of MT1 and RT were dependent on type I interferon signaling. CONCLUSIONS: These data shed new light on the role of TGFß in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGFßR inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Transforming Growth Factor beta / Tumor-Associated Macrophages Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals / Humans Language: En Journal: J Immunother Cancer Year: 2022 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Transforming Growth Factor beta / Tumor-Associated Macrophages Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals / Humans Language: En Journal: J Immunother Cancer Year: 2022 Document type: Article Affiliation country: Country of publication: