Tanita Kayo, Fujimura Taku, Sato Yota, Lyu Chunbing, Kambayashi Yumi, Ogata Dai, Fukushima Satoshi, Miyashita Azusa, Nakajima Hideki, Nakamura Motoki, Morita Akimichi, Aiba Setsuya
Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Dermatology, Saitama Medical University, Saitama, Japan.
Front Oncol. 2019 Sep 20;9:907. doi: 10.3389/fonc.2019.00907. eCollection 2019.
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 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 . 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.
贝沙罗汀是一种第三代视黄酸X受体选择性维甲酸，已被批准用于治疗早期和晚期皮肤T细胞淋巴瘤（CTCL）。尽管贝沙罗汀已用于治疗CTCL数十年，但对于其在CTCL患者中的抗肿瘤作用机制知之甚少。因此，本研究使用EL4小鼠T细胞淋巴瘤模型，重点研究贝沙罗汀的免疫调节作用，随后对接受贝沙罗汀治疗的CTCL患者进行调查。腹腔注射贝沙罗汀可显著降低肿瘤微环境中CCL22、CXCL5、CXCL10和p19的表达。基于这些结果，我们随后评估了25例CTCL患者血清中CCL22、CXCL5和CXCL10的水平，发现晚期CTCL患者的CCL22水平显著高于早期CTCL患者。接下来，我们评估了接受贝沙罗汀治疗的CTCL患者血清中CCL22、CXCL5和CXCL10的水平。80%对贝沙罗汀治疗有反应的CTCL患者血清CCL22水平显著降低。此外，免疫荧光染色显示CD163 M2巨噬细胞是CCL22的主要来源。此外，贝沙罗汀可降低单核细胞产生的M2巨噬细胞分泌CCL22的水平。我们的研究结果表明，贝沙罗汀的临床益处部分归因于对M2极化肿瘤相关巨噬细胞分泌CCL22的抑制作用。
