Targeting Cancer Cell Ccr2 Enhances Synergistic Immune Surveillance In Breast Cancer.

High expression of the C-C chemokine receptor type 2 (CCR2) in tumor samples and serum correlates with poor prognosis in human breast cancer, which has sparked interest in targeting the CCR2 pathway for therapeutic benefit. Importantly, a human CCR2 inhibitor (PF-04136309) has been investigated in clinical trials, and is currently being studied in a phase 1b/2 trial for pancreatic cancer (NCT02732938). Previous studies have focused on the protumor effects of CCR2 signaling in inflammatory monocytes. However, CCR2 is also expressed in breast cancer cells, but its potential function in cancer cells is poorly understood. To determine the specific roles of CCR2 in cancer and host cells, respectively, we established an orthotopic breast cancer mouse model by injecting primary cancer cells from MMTV-PyMT; Ccr2 +/+ or MMTV-PyMT; Ccr2 -/- mice into the mammary glands of wide-type or Ccr2 null hosts. In this cancer model, deleting Ccr2 in host cells, including monocytes, did not alter tumor growth. However, when tumor cells had lost Ccr2 , immune surveillance was much more efficient, with greater infiltration and expansion of cytotoxic CD8 + T cell lymphocytes (CTLs) that efficiently recognized and destroyed the cancer cells, resulting in significant inhibition of tumor growth. Consistently, the delayed tumor growth of Ccr2 null cancer cells was fully reversed when these same cancer cells were transplanted into athymic (immunodeficient) mice. The reduced growth of tumors derived from Ccr2 -/- cancer cells was associated with upregulation of IFN-γ response genes and genes involved in MHC class I presentation, as well as decreased expression of checkpoint inhibitor PD-L1 in cancer cells. Finally, greater infiltration of CD103 + dendritic cells (DCs) in Ccr2 -/- tumor microenvironment also contributed to increased CTL function by cross presentation. Taken together, our results show that CCR2-expressing breast cancer cells orchestrated global changes in the infiltration of CTLs and DCs, leading to effective immune suppression. This suggests that CCR2 may be an immunotherapeutic target in breast cancer. Citation Format: Miriam R. Fein, Xue-Yan He, Ana S. Almeida, Arnaud Pommier, Emilis Bružas, Anais Eberhardt, John Erby Wilkinson, Camila dos Santos, Mikala Egeblad. Targeting cancer cell CCR2 enhances synergistic immune surveillance in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B42.