Upregulation of the Chemokine Receptor CCR4 in Cutaneous T-Cell Lymphoma and Nodal T-Cell Lymphoma: Implications for Targeted Therapy.

The chemokine receptor CCR4 is expressed by a minor population of non-neoplastic T-cells, particularly Th2 helper T-cells, skin-homing T-cells and CD4+CD8− thymocytes. To assess the suitability of this receptor as a target for immunotherapy, we compared expression of CCR4 in a large series of T-cell malignancies with non-neoplastic T-cells by immunohistochemistry on formalin-fixed, paraffin-embedded material. Using tissue arrays and whole tissue sections, we assessed CCR4 levels in 233 biopsy samples from 182 patients with various T-cell tumors, particularly mycosis fungoides (MF, n = 54) and Sezary syndrome (SS, n = 15). We utilized the anti-CCR4 antibody KM2160 (Kyowa Hakko Kogyo, Tokyo, Japan), whose specificity has been established by immunoprecipitation and flow cytometry on CCR4-expressing transfectants and T-cell lines. Immunostaining was graded on a 4-tier scale (negative, focal, partial and uniform positivity) and compared with staining for markers of tumor progression including CD25, CD30 and the cytotoxic marker granzyme B and with a mediator of lymphocyte homing to skin, cutaneous lymphocyte antigen (CLA). Overall, CCR4 was expressed either partially or uniformly in 49% of T-cell tumors. Among MF/SS cases, partial or uniform CCR4 expression was found in 52% of cases, including in both early patch/plaque stage lesions and disseminated disease. CCR4 was upregulated upon large cell transformation in 39% of 23 MF/SS cases studied in sequential biopsies. There was an 80% concordance rate in CCR4 staining patterns in tumor cells in biopsies taken simultaneously from different anatomic sites. Upregulation of CCR4 upon large cell transformation was independent of other markers of progression, including CD25, CD30 and granzyme B but was significantly correlated with the degree of CLA expression. In contrast to the strong intensity of CCR4 staining in MF/SS cases, dimmer more variable expression was seen in skin homing T-cells in 94% of chronic dermatitis cases (n = 18). Among other T-cell tumors, CCR4 expression was common in AIL (70%), ALCL (53%) and PTCL unspecified (55%) and in the more mature subset of precursor-T lymphoblastic lymphoma/leukemia. CCR4-expressing T-cells were rare in 12 lymph node biopsies with reactive lymphadenitis. In conclusion, the chemokine receptor CCR4 is stably upregulated in cutaneous lymphoma and nodal T-cell lymphoma as compared to levels seen in non-neoplastic T-cells and thus represents a promising antigen for selective targeting of T-cell malignancies by immunotherapy.