Tumor microenvironments posses complex chemokine networks that contribute to the extent and phenotype of the host infiltrate. Malignant cells may gain functional chemokine receptors, often as a consequence of oncogenic mutations, allowing them to respond to distant chemokine gradients during metastasis. The chemokine receptor CCR4 was highly expressed in human renal cell carcinoma, RCC, biopsies and RCC patient plasma had abnormal levels of CCR4 ligands. However, during pre-clinical evaluation of CCR4 as a target in RCC, we found that both a small molecule CCR4 inhibitor and an anti-CCR4 antagonistic antibody had unexpected and novel anti-tumor activity in the mouse RCC RENCA model. CCR4 antagonists did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cells and Th1 cytokine levels, as well as reducing splenic MDSC infiltrate, and blood chemokine levels. Although the most prominent changes were in the myeloid compartment, anti-tumor activity was lost in athymic mice, supporting a role for the adaptive immune system in CCR4 antagonist action. CCR4 antagonists, alone, or in combination with other immune modulators, may be of interest in human cancers with high levels of tumor CCR4 and abnormal plasma CCR4 ligand levels.

Citation Format: Chiara Berlato, Moddasar N. Kahn, Tiziana Schioppa, Richard Thompson, Eleni Maniati, Monica Canosa, Hagen Kulbe, Chris Sheldon, Keith Wreggett, Urs Hagemann, Alexander Duncan, Laura Fletcher, Robert W. Wilkinson, Thomas Powles, Sergio Quezada, Frances Balkwill. Antagonists of the chemokine receptor CCR4 reverse the tumor-promoting microenvironment of renal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1076. doi:10.1158/1538-7445.AM2014-1076