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CCR2/CCR5

Chemokine (C-C motif) receptors 2 (CCR2) and 5 (CCR5) can promote trafficking of immunosuppressive cells and suppress T-cell function. CCR2/CCR5 inhibition may decrease tumor infiltration of these immunosuppressive cells.

Expression and normal function

CCR2 and CCR5 are both expressed on T cells, Tregs, monocytes, MDSCs, and TAMs^1-6

CCR2 and CCR5 regulate the recruitment of immunosuppressive cells through the stroma^7,8
The ligands for CCR2 and CCR5 are chemokine (C-C motif) ligand 2 (CCL2) and 5 (CCL5), respectively^3,7

CCL2 and CCL5, expressed by tumor and stromal cells, promote the trafficking and infiltration of immunosuppressive Tregs, TAMs, and MDSCs, by interacting with the CCR2 and CCR5, respectively, on these
cells.^{2,3,6-8,10,11}

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Role in cancer

Tumors use CCR2 signaling to mobilize inflammatory monocytes from the bone marrow into the blood and to sites of inflammation, where they infiltrate the tumor microenvironment^9,11,12

These monocytes can differentiate into protumor macrophages, such as TAMs, that suppress cytotoxic T-cell proliferation and function.^9,11,12

CCR5 can stimulate the differentiation of monocytes into protumor TAMs as well as induce MDSC differentiation⁷
CCR2, CCR5, and their ligands may be elevated in certain advanced solid tumors and may enhance tumor cell survival^9,13,14

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Preclinical evidence

Preclinical data suggest that depletion or blockade of CCR2 and CCR5, individually or in combination, decreases the infiltration of MDSCs, TAMs, and Tregs into the tumor microenvironment^10,11,15-17

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REFERENCES–CCR2/CCR5

1. de Oliveira CEC, Oda JMM, Guembarovski RL, et al. CC chemokine receptor 5: the interface of host immunity and cancer. Dis Markers. 2014;2014:126954. doi:10.1155/2014/126954. 2. Lesokhin AM, Hohl TM, Kitano S, et al. Monocytic CCR2+ myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res. 2012;72(4):876-886. 3. Lim HW, Lee J, Hillsamer P, Kim CH. Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J Immunol. 2008;180(1):122-129. 4. Mack M, Cihak J, Simonis C, et al. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J Immunol. 2001;166(7):4697-4704. 5. Sica A, Saccani A, Bottazzi B, et al. Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. J Immunol. 2000;164(2):733-738. 6. Umansky V, Blattner C, Gebhardt C, Utikal J. CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma. Cancer Immunol Immunother. 2017;66(8):1015-1023. 7. Weitzenfeld P, Ben-Baruch A. The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett. 2014;352(1):36-53. 8. Huang B, Lei Z, Zhao J, et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 2007;252(1):86-92. 9. Lim SY, Yuzhalin AE, Gordon-Weeks AN, Muschel RJ. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget. 2016;7(19):28697-28710. 10. Chang L-Y, Lin Y-C, Mahalingam J, et al. Tumor-derived chemokine CCL5 enhances TGF-β-mediated killing of CD8+ T cells in colon cancer by T-regulatory cells. Cancer Res. 2012;72(5):1092-1102. 11. Sanford DE, Belt BA, Panni RZ, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013;19(13):3404-3415. 12. Franklin RA, Liao W, Sarkar A, et al. The cellular and molecular origin of tumor-associated macrophages. Science. 2014;344(6186):921-925. 13. Loberg RD, Ying C, Craig M, Yan L, Snyder LA, Pienta KJ. CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia. 2007;9(7):556-562. 14. Wolf MJ, Hoos A, Bauer J, et al. Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell. 2012;22(1):91-105. 15. Tan MCB, Goedegebuure PS, Belt BA, et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 2009;182(3):1746-1755. 16. Kitamura T, Qian B-Z, Soong D, et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med. 2015;212(7):1043-1059. 17. Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11(6):e0158156. doi:10.1371/journal.pone.0158156.