Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma.

Kayo Tanita,Yumi Kambayashi,Akimichi Morita,Dai Ogata,Taku Fujimura,Yota Sato,Satoshi Fukushima,Chunbing Lyu,Motoki Nakamura,Setsuya Aiba,Azusa Miyashita,Hideki Nakajima

doi:10.3389/fonc.2019.00907

Abstract

Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved 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 expressions 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 CD163+ M2 macrophages as the main source of CCL22. 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.

Highlights

Most cutaneous T-cell lymphomas (CTCLs) start as an indolent disease that progresses slowly, but advances to skin tumors followed by lymph node and visceral involvements [1]
Evaluating the immunological background of CTCL is important, and this study 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
Since the immunological microenvironment of CTCL resembles that of atopic dermatitis [16,17,18], and as tumor-associated macrophages (TAMs) have been reported to play a significant role in stimulating the developing tumor microenvironment by periostin and IL-4 in lesional skin of mycosis fungoides (MF) [16], we hypothesized that bexarotene might affect the immunological functions of TAMs in tumor sites of CTCL

Summary

Introduction

Most cutaneous T-cell lymphomas (CTCLs) start as an indolent disease that progresses slowly, but advances to skin tumors followed by lymph node and visceral involvements [1]. The optimal first-line therapy for advanced CTCL has remained unclear. Such reports suggested the importance of evaluating the production of CCR4 ligands CCL17 and CCL22 in the tumor microenvironment of CTCL. According to these preclinical studies, malignant T cells in CTCL have been shown to exhibit features of the regulatory T-cell (Treg) phenotype, Th2 phenotype, and Th17 phenotype [5], suggesting that Tregs and Th2-related factors, and Th17-related factors are important in understanding the immunological background of CTCL

Methods

Results

Conclusion