Retinoid Exposure Decreases Foxp3 Expression in Cutaneous T‐cell Lymphoma

Abstract

Retinoids, natural and synthetic vitamin A derivatives, activate members of the RAR and RXR subfamilies of transcription factors to promote cellular differentiation. Exploiting retinoids to induce differentiation embodies a milestone in cancer therapeutics. The success is championed by remarkable outcomes achieved upon the advent of retinoid regimens with acute promyelocytic leukemia (APL). While retinoids have been used for over 3 decades to treat cutaneous T‐cell lymphoma (CTCL), it remains unknown if retinoid‐dependent changes in differentiation accounts for the clinical benefit in CTCL as occurs with APL. Delineating the mechanism of action of retinoid‐based treatment in CTCL merits addressing considering that a lack of specificity contributes to metabolic sequelae that require ceasing treatment. The heterogeneity of the CTCL etiology further frustrates efforts as the exact classification of the T‐cell nature of CTCL is varied and largely debated. We first identify that CTCL lines express the hallmark Treg marker Foxp3, whereas lymphoma lines not of CTCL origin lack Foxp3 expression. We found that various synthetic and natural retinoids, including Bexarotene, an RXR agonist and the only FDA‐approved retinoid for CTCL treatment, induce a dose‐dependent decrease in Foxp3 expression in six different human CTCL cell lines. Changes in Foxp3 expression occurred at lower retinoid doses and shorter exposure times than are required to induce apoptosis. In addition, RAR and RXR receptors function synergistically to reduce Foxp3 expression at very low doses and abbreviated exposure times. Indeed, the decrement in Foxp3 expression is abrogated upon retinoid removal, demonstrating that diminished Foxp3 protein expression is not an artifact of cell death. Prior work by our group has shown that the RAR‐alpha receptor subtype prompts gut‐tropic adhesion and chemotactic changes with CTCL. We now show that the RAR‐alpha receptor subtype, assessed using selective receptor agonists and antagonists, transduces the observed changes in Foxp3 expression. This work establishes that the differentiation marker of Tregs is routinely expressed by CTCL cell lines, and that therapeutic retinoids decrease the abundance of this protein marker. It remains to be determined if the retinoid‐induced differentiation of CTCL forces a phenotype that is incompatible with cutaneous localization and predisposes the cells to apoptosis. Alternatively, retinoid‐forced differentiation of cells with a terminally differentiated phenotype, like CTCL, may trigger apoptosis. Furthermore, future work will determine if this newly identified consequence of retinoid exposure to alter differentiation markers in CTCL has clinical ramifications reminiscent of APL.Support or Funding InformationFunding provided by the BREA program at the Arkansas Colleges of Health Education