Bexarotene blunts malignant T-cell chemotaxis in Sezary syndrome: reduction of chemokine receptor 4-positive lymphocytes and decreased chemotaxis to thymus and activation-regulated chemokine.
The malignant cells in Sezary syndrome express the skin trafficking molecules' cutaneous lymphocyte associated antigen (CLA) and chemokine receptor 4 (CCR4). High levels of the CCR4 ligand, thymus, and activation-regulated chemokine (TARC), have been reported in the blood and skin of patients. The rexinoid X-receptor specific retinoid, bexarotene, has contributed to the resolution of cutaneous disease among patients. To evaluate the effects of bexarotene on skin trafficking molecule expression and chemotaxis, peripheral blood mononuclear cells from Sezary syndrome patients and healthy controls were treated with bexarotene in vitro. CCR4 and CLA expression levels and chemotaxis in response to TARC (6.25 ng/ml) were evaluated among lymphocytes before and after treatment with bexarotene (10 microM). Flow cytometric analysis was performed to evaluate CD4, CD26, CLA, and CCR4 cell surface expression. Transwell migration assays were performed to evaluate chemotaxis to TARC. Prior to treatment, malignant cells exhibited higher CCR4 expression (45-90%) and greater than four times more chemotaxis to TARC compared with healthy controls. After treatment with bexarotene for 36-96 hr, a 28% reduction in CCR4 expression was noted (P < 0.05) among the malignant population with an associated 9% decrease in chemotaxis to TARC (P < 0.05). Our results show that bexarotene may inhibit malignant cell trafficking to the skin through an ability to suppress CCR4 expression among Sezary syndrome lymphocytes.
Richardson
Stephen K
SK
Department of Dermatology, University of Pennsylvania, Philadelphia, Pennysylvania, USA.
Newton
Sarah B
SB
Bach
Tami L
TL
Budgin
Jeanne B
JB
Benoit
Bernice M
BM
Lin
Julie H
JH
Yoon
Jessica S
JS
Wysocka
Maria
M
Abrams
Charles S
CS
Rook
Alain H
AH
D000368:Aged; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000077610:Bexarotene; D016022:Case-Control Studies; D002478:Cells, Cultured; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000276:immunology* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D012751:Sezary Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013997:Time Factors
D016588:Anticarcinogenic Agents; C106230:CCL17 protein, human; C515354:CCR4 protein, human; D054414:Chemokine CCL17; D019742:Chemokines, CC; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene