CCR2-Dependent Recruitment of Tregs and Monocytes Following Radiotherapy Is Associated with TNFα-Mediated Resistance

Cancer Immunol Res. 2019 Mar;7(3):376-387. doi: 10.1158/2326-6066.CIR-18-0633. Epub 2019 Jan 29.


Radiotherapy (RT) represents one of the main anticancer approaches for the treatment of solid tumors. Beyond the expected direct effects of RT on tumor cells, evidence supporting the importance of an immune response to RT is growing. The balance between RT-mediated immunogenic and tolerogenic activity is ill-defined and deserves more attention. Herein, a murine model of head and neck squamous cell carcinoma was used to demonstrate that RT upregulated CCL2 chemokine production in tumor cells, leading to a CCR2-dependent accumulation of tumor necrosis factor alpha (TNFα)-producing monocytes and CCR2+ regulatory T cells (Treg). This corecruitment was associated with a TNFα-dependent activation of Tregs, dampening the efficacy of RT. Our results highlight an unexpected cross-talk between innate and adaptive immune system components and indicate CCL2/CCR2 and TNFα as potential clinical candidates to counterbalance the radioprotective action of monocyte-derived cells and Tregs, paving the way for potent combined radioimmunotherapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Disease Models, Animal
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / radiotherapy
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Radiation Tolerance / immunology*
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / immunology*
  • Receptors, CCR2 / metabolism
  • Squamous Cell Carcinoma of Head and Neck / immunology
  • Squamous Cell Carcinoma of Head and Neck / radiotherapy
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Tumor Microenvironment / immunology
  • Tumor Microenvironment / radiation effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / metabolism


  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Receptors, CCR2
  • Tnf protein, mouse
  • Tumor Necrosis Factor-alpha