TGFβ receptor inhibition unleashes interferon-β production by tumor-associated macrophages and enhances radiotherapy efficacy

• DOI: 10.1136/jitc-2021-003519
• Publication Date: 2022-03-17T17:11:54Z
• Authors: Pauline Hamon; Marine Gerbé De T...; Marion Classe; Nicolas Signolle; Winchygn Liu; Olivia Bawa; Lydia Meziani; Céline Clémenson; Fabien Milliat; Eric Deutsch; Michele Mondini
• Keywords: 0301 basic medicine; 0303 health sciences; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Basic Tumor Immunology; Interferon-beta; 3. Good health; Mice; 03 medical and health sciences; Transforming Growth Factor beta; Cell Line, Tumor; Tumor-Associated Macrophages; Animals; Humans; Receptors, Transforming Growth Factor beta; RC254-282

Background Transforming growth factor-beta (TGFβ) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association TGFβ with impaired T cell infiltration and antitumor immunity is known, but mechanisms which participates in immune exclusion limits therapies warrant further investigations. Methods We used clinically relevant receptor 2 (TGFβR2)-neutralizing antibody MT1 small molecule TGFβR1 inhibitor LY3200882 evaluated their combination RT against murine orthotopic models head neck lung cancer. Results demonstrated that pathway inhibition strongly increased RT. TGFβR2 upregulated interferon beta expression tumor-associated macrophages within irradiated tumors favored at periphery core lesions. highlighted both lymphocyte observed were dependent on type I signaling. Conclusions These data shed new light role limiting RT, identifying a novel mechanism involving macrophage-derived production, fostering use TGFβR therapeutic strategies for management