CCR2 Influences T Regulatory Cell Migration to Tumors and Serves as a Biomarker of Cyclophosphamide Sensitivity.

The CCL2 chemokine receptor CCR2 drives cancer by mediating the recruitment of monocytes and myeloid-derived suppressor cells to the tumor microenvironment. In this study, we extend the significance of CCR2 in this setting by identifying a new role for it in mediating recruitment of CD4 T regulatory cells (Treg). Following tumor initiation, an expanded population of CCR2 Tregs required CCR2 expression to traffic between draining lymph nodes (dLN) and the tumor. This Treg subset was enriched in the fraction of tumor antigen-specific cells in the dLN, where they displayed an activated immunosuppressive phenotype. Notably, in mouse models, low-dose cyclophosphamide treatment preferentially depleted CCR2 Treg, enhancing priming of tumor-specific CD8 T cells. In the MMTV-PyMT transgenic mouse model of breast cancer and in oral squamous cell carcinoma patients, tumor development was associated with decreased blood frequency and inversely increased tumor frequency of CCR2 Tregs. Our results define a novel subset of CCR2 Treg involved in tumoral immune escape, and they offer evidence that this Treg subset may be preferentially eradicated by low-dose cyclophosphamide treatment. Cancer Res; 76(22); 6483-94. ©2016 AACR.