Immunopathogenesis of lymphoma: focus on CCR4.

Evading immune surveillance is one of the common hallmarks of cancer. Herein we describe two major evasion mechanisms in lymphoma, focusing on regulatory T (Treg) cells and C-C chemokine receptor 4 (CCR4) expressed on these cells. First, the tumor cells themselves function as Treg cells, characterized by expression of CCR4, contributing to tumor survival by downregulating host immunity. Second, CCR4 ligands are produced by tumor cells, which attract other CCR4(+) Treg cells to the vicinity of the tumor. CCR4(+) adult T-cell leukemia//lymphoma is an example of the former phenomenon, and Hodgkin lymphoma of the latter, for which an almost identical immunopathogenesis has been reported in many types of cancer. Awareness of the importance of CCR4 allows the rational design of more effective cancer treatments. Accordingly, we have developed a defucosylated anti-CCR4 mAb, the first therapeutic agent targeting CCR4 to be used clinically for cancer. The therapeutic anti-CCR4 mAb represents a promising treatment method for patients with CCR4(+) neoplasms by directly killing the cancer cells, but could also be used as a novel treatment strategy for many types of CCR4(-) cancers to overcome the suppressive effect of CCR4(+) Treg cells.