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

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.

Cellular Interactions and Inflammation in the Pathogenesis of Cutaneous T-Cell Lymphoma

“…In addition, Th2 cytokines are known to stimulate the secretion of CCL18 and CCL22 from antigen-presenting cells ( Vulcano et al, 2001 ; van Lieshout et al, 2006 ; Tsicopoulos et al, 2013 ; Furudate et al, 2016 ). These chemokines are indeed expressed by macrophages and DCs in CTCL skin lesions and the levels of CCL18 correlate with those of IL-4 ( Gunther et al, 2011 ; Miyagaki et al, 2013 ; Tanita et al, 2019 ; Vieyra-Garcia et al, 2019 ). A recent study provided evidence suggesting that lesional c-Kit + DCs recruit benign Th2 cells via secretion of CCL18 which leads to formation of an inflammatory synapse between the DCs, benign Th2 cells and the malignant T cells ( Vieyra-Garcia et al, 2019 ).…”

“…DCs in CTCL skin lesions and the levels of CCL18 correlate with those of IL-4 (Gunther et al, 2011;Miyagaki et al, 2013;Tanita et al, 2019;Vieyra-Garcia et al, 2019). A recent study provided evidence suggesting that lesional c-Kit + DCs recruit benign Th2 cells via secretion of CCL18 which leads to formation of an inflammatory synapse between the DCs, benign Th2 cells and the malignant T cells (Vieyra-Garcia et al, 2019).…”

Successful treatment of mogamulizumab‐resistant mycosis fungoides with mogamulizumab plus etoposide combined therapy: Investigation of the immunomodulatory effects of etoposide on the tumor microenvironment

“…Notably, there was no increase of CCL22 mRNA expression. Since CCL22 is reported to correlate with the progression of CTCL, 6 etoposide might be an ideal drug for immunomodulation of the CTCL microenvironment. Since mogamulizumab is cytotoxic against CCR4+ lymphoma cells by ADCC that depends on the contact between lymphoma cells and effector cells, increased levels of CCL17, CXCL5, and CXCL10 might enhance the therapeutic effect of mogamulizumab.…”

A skin liquid biopsy method to assess the immune environment of cutaneous T-cell lymphoma

“…We found that CCL17, as well as the other CCR4 ligand, CCL22, strongly correlated with mSWAT, with a more pronounced effect observed in lesional blood than in peripheral blood (Figure 3d). The serum level of CCL22 reportedly decreases following treatment with bexarotene 17 . In this study, bexarotene combined with phototherapy caused a decrease in CCL22 levels in lesional blood, but not in peripheral blood ( Figure 6d, e).…”