Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma
Open Access
- 20 September 2019
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Oncology
- Vol. 9, 907
- https://doi.org/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.Keywords
Funding Information
- Japan Agency for Medical Research and Development
This publication has 27 references indexed in Scilit:
- Expression of CCR3 and CCR4 Suggests a Poor Prognosis in Mycosis Fungoides and Sézary SyndromeActa Dermato Venereologica, 2019
- Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trialThe Lancet Oncology, 2018
- The retinoid X receptor agonist, 9-cis UAB30, inhibits cutaneous T-cell lymphoma proliferation through the SKP2-p27kip1 axisJournal of Dermatological Science, 2018
- Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International ConsortiumAnnals of Oncology, 2017
- Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphomaOncotarget, 2016
- Tumor microenvironment in mycosis fungoides and Sézary syndromeCurrent Opinion in Oncology, 2016
- U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphomaBritish Journal of Dermatology, 2012
- WHO-EORTC classification for cutaneous lymphomasBlood, 2005
- Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action.2002
- Bexarotene Is Effective and Safe for Treatment of Refractory Advanced-Stage Cutaneous T-Cell Lymphoma: Multinational Phase II-III Trial ResultsJournal of Clinical Oncology, 2001