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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00907

Bexarotene reduces production of CCL22 from tumor-associated macrophages in cutaneous T-cell lymphoma

Kayo Tanita1,  Taku Fujimura1*,  Yota Sato1,  Lyu Chunbing1,  Yumi Kambayashi1,  Dai Ogata2,  Satoshi Fukushima3,  Azusa Miyashita3, Hideki Nakajima4, Motoki Nakamura5, Akimichi Morita5 and Setsuya Aiba1
  • 1Department of Dermatology, School of Medicine, Tohoku University, Japan
  • 2Department of Dermatology, Saitama Medical University, Japan
  • 3Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Japan
  • 4Department of Dermatology, Medical School, Kōchi University, Japan
  • 5Department of Geriatric and Environmental Dermatology, Nagoya University Graduate School of Medicine, Japan

Bexarotene is a third-generation retinoid X receptor-selective retinoid that is permitted for use in the treatment of both early and advanced cutaneous T cell lymphoma (CTCL). Although bexarotene has been used for decades in the treatment of CTCL, little is known about the mechanisms underlying its anti-tumor effects in CTCL patients. This study therefore focused on the immunomodulatory effects of bexarotene in vivo using an EL4 mouse T-cell lymphoma model, followed by investigation in CTCL patients treated with bexarotene. Intraperitoneal injection of bexarotene significantly decreased expression of CCL22, CXCL5, CXCL10 and p19 in the tumor microenvironment. Based on those results, we then evaluated serum levels of CCL22, CXCL5 and CXCL10 in 25 patients with CTCL, revealing that CCL22 was significantly increased in advanced CTCL compared with early CTCL. Next, we evaluated serum levels of CCL22, CXCL5 and CXCL10 in CTCL patients treated with bexarotene. Serum levels of CCL22 were significantly decreased in 80% of CTCL patients who responded to bexarotene therapy. In addition, immunofluorescence staining revealed that the main source of CCL22 was CD163+ M2 macrophages. Moreover, bexarotene decreased the production of CCL22 by M2 macrophages generated from monocytes in vitro. Our findings suggest that the clinical benefits of bexarotene are partially attributable to suppressive effects on the production of CCL22 by M2-polarized tumor-associated macrophages.

Keywords: advanced CTCL, Bexarotene, Tumor-associated macrophages, CCL22, Immunomodulation

Received: 30 Apr 2019; Accepted: 02 Sep 2019.

Copyright: © 2019 Tanita, Fujimura, Sato, Chunbing, Kambayashi, Ogata, Fukushima, Miyashita, Nakajima, Nakamura, Morita and Aiba. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Taku Fujimura, School of Medicine, Tohoku University, Department of Dermatology, Sendai, Japan, tfujimura1@mac.com