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Beyond the expected direct effects of radiation therapy (RT ) on tumor cells, several evidence support the importance of an immune response to radiotherapy. These observations foster the use of combination of immunomodulators with RT to enhance its therapeutic index. Several efforts have been put to investigate the induction of an antitumor-immunity by RT. Nevertheless, RT can also induce or amplify tumor immunosuppressive mechanisms. The balance between RT-mediated immunogenic and immunosuppressive activities deserves more attention. Infiltration of monocytes/macrophages and regulatory T cells (Tregs) into the tumor is a known factor limiting the antitumor immune response. Among the many cytokines secreted by tumor cells, CCL2 is involved in monocyte recruitment from bone marrow to the inflammatory site, as well as a subset of Tregs. We thus speculated that the CCL2/CCR2 axis might be implicated in the co-recruitment of TAMs and Tregs following RT, favoring immunosuppression.

We used orthotopic models of oral and lung cancer in immunocompetent mice to evaluate the effects of irradiation on monocytes and Tregs recruitments to tumors. Flow cytometry and histological analysis were performed. Cytokine profiling and ELISA analyses were performed on tumor tissues and blood samples. Transgenic mice bearing fluorescent reporters allowed us to identify target cells by confocal and intravital biphoton microscopy. Mice knockout (KO) for CCL2 or CCR2 were used to investigate the respective role of the chemokine pathway in the response to radiotherapy, as well as mice selectively depleted of Tregs (Foxp3-DTR mice) to analyze their contribution to the resistance to RT.

Radiotherapy strongly upregulated CCL2 chemokine production in tumor cells. This resulted in an accumulation of monocytes and of a subset of CCR2-positive Tregs in the tumor bed of voth oral and lung tumors, and a dynamic physical interaction between these cells was identified. CCR2-KO mice and mice conditionally depleted of Tregs had an improved response to radiotherapy. Recruited monocytes produced TNFα, which contributed to the activation of Tregs. In agreement with this observation, anti-TNFα treatment increased the efficacy of RT.

We propose that reducing radiation-induced monocyte and Trges recruitment may yield improved results in the treatment of head and neck and lung carcinomas by radiotherapy. We thus indicate CCL2/CCR2 and TNFα as potential clinical candidates to counteract the radioprotective action of monocyte-derived cells and Tregs, paving the way for effective combined immunoradiotherapies. As modulators of CCL2, CCR2 and TNFα are already being tested in clinical settings, the results from this study can be transferred into the clinic.  Immunologically-augmented radiotherapy could also allow the reduction of the delivered radiation dose, thus minimizing the risk of treatment sequelae while maintaining optimal tumor control.