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.

Biological effects of bexarotene in cutaneous T-cell lymphoma.

OBJECTIVE: To determine the effects of bexarotene on malignant T cells isolated from the peripheral blood of patients with the leukemic variant of cutaneous T-cell lymphoma (Sézary syndrome). DESIGN, SETTING, AND PARTICIPANTS: Peripheral blood mononuclear cells from 9 patients with Sézary syndrome and a high burden of circulating malignant T cells (>50% of peripheral blood mononuclear cells) and 6 healthy volunteers underwent evaluation at a university medical center, to test the effects of bexarotene on T cells. MAIN OUTCOME MEASURES: The capacity of bexarotene to induce apoptosis and its effects on T-cell cytokine production from peripheral blood lymphocytes isolated from patients with Sézary syndrome. RESULTS: Bexarotene produced dose-dependent apoptosis of peripheral blood T cells from patients with Sézary syndrome. The T cells from approximately two thirds of patients were consistently sensitive to bexarotene, whereas those from the remaining one third of patients were consistently resistant to the apoptotic effects of bexarotene. Bexarotene inhibited mitogen-induced interleukin 4 production by the peripheral blood cells of patients with Sézary syndrome, and this effect correlated with sensitivity of patients' cells to apoptosis. In contrast to the retinoic acid receptor-specific retinoid, all-trans retinoic acid, bexarotene does not induce the augmentation of interferon gamma production. CONCLUSIONS: Bexarotene induces apoptosis of malignant T cells from patients with Sézary syndrome, but the cells from a proportion of patients are resistant to the apoptotic effects. Interleukin 4 production, which can play a role in the systemic immunosuppression that characterizes advancing Sézary syndrome, may be inhibited by bexarotene.