CCR4 as a Therapeutic Target for Cancer Immunotherapy

SIMPLE SUMMARY: CCR4 is a chemokine receptor selectively expressed on normal T cell subsets such as type 2 helper T cells, skin-homing T cells and regulatory T cells, and on skin-associated T cell malignancies such as adult T cell leukemia/lymphoma (ATLL), which is etiologically associated with human T lymphocyte virus type 1 (HTLV-1), and cutaneous T cell lymphomas (CTCLs). Mogamulizumab is a fully humanized and glyco-engineered monoclonal anti-CCR4 antibody used for the treatment of refractory/relapsed ATLL and CTCLs, often resulting in complete remission. The clinical applications of Mogamulizumab are now being extended to solid tumors, exploring the therapeutic effect of regulatory T cell depletion. This review overviews the expression of CCR4 in various T cell subsets, HTLV-1-infected T cells, ATLL and CTCLs, and the clinical applications of Mogamulizumab. ABSTRACT: CCR4 is a chemokine receptor mainly expressed by T cells. It is the receptor for two CC chemokine ligands, CCL17 and CCL22. Originally, the expression of CCR4 was described as highly selective for helper T type 2 (Th2) cells. Later, its expression was extended to other T cell subsets such as regulatory T (Treg) cells and Th17 cells. CCR4 has long been regarded as a potential therapeutic target for allergic diseases such as atopic dermatitis and bronchial asthma. Furthermore, the findings showing that CCR4 is strongly expressed by T cell malignancies such as adult T cell leukemia/lymphoma (ATLL) and cutaneous T cell lymphomas (CTCLs) have led to the development and clinical application of the fully humanized and glyco-engineered monoclonal anti-CCR4 Mogamulizumab in refractory/relapsed ATLL and CTCLs with remarkable successes. However, Mogamulizumab often induces severe adverse events in the skin possibly because of its efficient depletion of Treg cells. In particular, treatment with Mogamulizumab prior to allogenic hematopoietic stem cell transplantation (allo-HSCT), the only curative option of these T cell malignancies, often leads to severe glucocorticoid-refractory graft-versus-host diseases. The efficient depletion of Treg cells by Mogamulizumab has also led to its clinical trials in advanced solid tumors singly or in combination with immune checkpoint inhibitors. The main focus of this review is CCR4; its expression on normal and malignant T cells and its significance as a therapeutic target in cancer immunotherapy.