TGF beta receptor inhibition unleashes interferon-beta production by tumor-associated macrophages and enhances radiotherapy efficacy

Background Transforming growth factor-beta (TGF beta) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGF beta with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGF beta participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations. Methods We used the clinically relevant TGF beta receptor 2 (TGF beta R2)-neutralizing antibody MT1 and the small molecule TGF beta R1 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 TGF beta pathway inhibition strongly increased the efficacy of RT. TGF beta R2 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 TGF beta 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 TGF beta R inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.