Abstract | May 5, 2021

Nuclear Receptor Synergism: A New Paradigm for Differentiation Therapy in Cutaneous T-cell Lymphoma

Presenting Author: Andrea Marie Powers, BS, First Year Medical Student, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas

Coauthors: Samuel L. Stahly, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Reid Cline, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Lauren A. Griffin, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Bryce Sarcar, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Alexis N. Danekas, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Nabila A. Siddiqui, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Lucas R. Johnson, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Sykes Martin, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Lance C. Bridges, PhD, Department of Biochemistry, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas, Abby L. Geis, PhD, Department of Immunology, Arkansas College of Osteopathic Medicine, Fort Smith, Arkansas

Learning Objectives

  1. Describe the parental structure of all retinoids;
  2. Discuss the potential clinical impact of receptor synergism in retinoid-based modalities for Cutaneous T-cell Lymphoma.

Background/Knowledge
Exploiting retinoids, natural and synthetic vitamin A derivatives, to induce cellular differentiation embodies a milestone in cancer therapeutics. Retinoids elicit the obligate changes in gene expression to drive differentiation through the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of ligand-dependent nuclear receptors. While retinoids have been used for over three decades to treat cutaneous T-cell lymphoma (CTCL), it remains unknown if retinoid dependent changes in differentiation, through RAR and RXR activity, account for the clinical benefit in CTCL.

Methods/Design
Protein expression analysis was performed by flow cytometry. We first identify that CTCL lines express the hallmark transcription factor for regulatory T (Treg) cells, FOXP3, whereas lymphoma lines not of CTCL origin lack FOXP3 expression.

Results/Findings
We found that various synthetic and natural retinoids, including Bexarotene, a pan-RXR agonist and the only FDA- approved retinoid for CTCL treatment, significantly decrease FOXP3 expression in six different human CTCL cell lines. We additionally delineate that the RAR and RXR isoforms account for the decreased FOXP3 response. Importantly, RAR and RXR receptors function synergistically to decrease FOXP3 expression.

Conclusion/Implications
This work establishes that the differentiation marker of Tregs is routinely expressed by CTCL cell lines, and that therapeutic retinoids decrease the expression of this transcription factor. Furthermore, the clarification of synergistic activity among select RAR and RXR isoforms provides justification for the further refinement of this proven CTCL treatment modality. Identifying the nuclear receptors that transduce retinoid exposure into CTCL cellular responses may reveal more specific points of therapeutic intervention that avoid the metabolic sequelae common to retinoid treatments.

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