Dataset Information

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.

SUBMITTER: Tanita K

PROVIDER: S-EPMC6763730 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Tanita Kayo K Fujimura Taku T Sato Yota Y Lyu Chunbing C Kambayashi Yumi Y Ogata Dai D Fukushima Satoshi S Miyashita Azusa A Nakajima Hideki H Nakamura Motoki M Morita Akimichi A Aiba Setsuya S

Frontiers in oncology 20190920

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 <i>in vivo</i> using an EL4 mouse T-cell lymphoma model, followed by investigation ...[more]

PMID: 31616630

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Project description:IntroductionCutaneous T-cell lymphoma (CTCL) is a chronic condition with low malignancy. The combined use of therapeutic agents and photo(chemo)therapy is widely applied for the treatment of CTCL. The efficacy and safety of bexarotene and photo(chemo)therapy combination therapy were previously confirmed in Japanese patients with CTCL. The efficacy and safety of the bexarotene and photo(chemo)therapy combination therapy was compared with bexarotene monotherapy in Japanese patients with CTCL.MethodsThis was a randomized, open-label, two-parallel-group, active-control specified clinical study in Japanese patients diagnosed with CTCL carried out over 8 weeks with a study extension conducted at two institutions. This study was registered in Japan Registry of Clinical Trials (jRCTs041180094).ResultsIn the combination therapy group, 22 subjects received oral bexarotene (300 mg/m2 body surface area) once daily, followed by bath-psoralen and ultraviolet (UV) A or narrowband UVB. In the monotherapy group, 24 subjects received oral bexarotene (300 mg/m2) once daily. The efficacy analysis using the modified Severity-Weighted Assessment Tool, which included 39 patients, showed a response rate of 81.0% (17/21) in the combination therapy group and 83.3% (15/18) in the monotherapy group. No statistically significant difference was detected between groups. In the combination therapy group, four subjects showed a complete clinical response or complete response, and subjects with a partial response exhibited a high rate of skin lesion resolution, significantly better than in the monotherapy group. In the safety analysis, which included 46 treated subjects (22 in the combination therapy group and 24 in the monotherapy group), no adverse events or adverse drug reactions were reported in either group.ConclusionBoth bexarotene and photo(chemo)therapy combination therapy and bexarotene monotherapy were therapeutically effective in Japanese patients with CTCL and well tolerated. Combination therapy led to a higher skin lesion resolution rate and greater therapeutic effects compared with monotherapy.Trial registrationjRCTs041180094.

Project description:Importance:Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. Objectives:To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. Design, Setting, and Participants:This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Main Outcomes and Measures:Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Results:Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P?=?.02). Conclusions and Relevance:These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.

Dataset Information

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

Publications

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

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