CCR4, the CC chemokine receptor 4, is a seven-transmembrane-type receptor. It serves as the receptor for two CC chemokine ligands, CCL17 and CCL22 [2]. Expressed predominantly by Th2 cells, cutaneous lymphocyte antigen-positive skin-homing T cells, Treg cells, and often highly expressed by mature T-cell neoplasms, CCR4 is involved in processes like cell migration and homing, and is thus of great biological importance in immunological and neoplastic diseases [2].

In murine models, CCR4+ Tregs were found to be the predominant Tregs recruited to hepatitis B-associated HCC (HBV + HCC), correlating with sorafenib resistance and HBV load titers [1]. These CCR4+ Tregs exhibited increased IL-10 and IL-35 expression, enhanced functionality in suppressing CD8+ T cells, and displayed PD-1+TCF1+ stem-like properties [1]. Treatment with a CCR4 antagonist or N-CCR4-Fc blocked intratumoral Treg accumulation, overcame sorafenib resistance, and sensitized tumors to PD-1 checkpoint blockade [1].

In conclusion, CCR4 plays a crucial role in the regulation of immune cell migration, especially of Tregs, which impacts the tumor microenvironment in diseases like HBV-associated HCC. Mouse models have been instrumental in revealing these functions, providing potential therapeutic targets for cancer immunotherapy by specifically blocking Treg infiltration into the tumor microenvironment [1].

References:

1. Gao, Yanan, You, Maojun, Fu, Junliang, Wang, Fu-Sheng, Yang, Pengyuan. 2021. Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B. In Journal of hepatology, 76, 148-159. doi:10.1016/j.jhep.2021.08.029. https://pubmed.ncbi.nlm.nih.gov/34689996/

2. Yoshie, Osamu, Matsushima, Kouji. 2014. CCR4 and its ligands: from bench to bedside. In International immunology, 27, 11-20. doi:10.1093/intimm/dxu079. https://pubmed.ncbi.nlm.nih.gov/25087232/