Retinoids Potentiate Clinically Relevant Cellular Responses through RARα/RXR Nuclear Receptor Synergism in Cutaneous T Cell Lymphoma

Abstract

The heterogeneity of cutaneous T cell lymphoma (CTCL) has stifled treatment options and hindered cure development. Despite the heterogeneous nature of CTCLs, a hallmark of all variants is malignant T cell infiltration of and/or proliferation within the skin. Therapeutic mechanisms aimed at resolving the shared attribute of dysregulated T cell trafficking embody an inclusive treatment with the broadest impact. Retinoids, natural and synthetic vitamin A derivatives, govern immune cell homing by inducing gut-specific receptors that naturally target cells away from the skin. Even though retinoids have been used to treat CTCL for over three decades, how the natural role of retinoids relates to therapeutic effectiveness is not known. In addition, the full clinical potential of retinoids is unrealized due to associated deleterious metabolic side effects, including hypertriglyceridemia, hypercholesterolemia, and hypothyroidism. Although the fundamentals of how retinoids activate ligand-dependent nuclear receptors to elicit immune cell responses are understood, the particular receptors that drive clinically beneficial outcomes (e.g. apoptosis) in malignant CTCLs are not known. This dissertation demonstrates that retinoids induce gut-specific trafficking receptors in CTCL variants, prior to the induction of apoptosis and growth inhibition. The current work delineates that heightened retinoid responsiveness is achieved through RARα/RXR synergism. Strikingly, as compared to current regiments, this novel approach accelerates CTCL apoptosis to occur in half the time with a 2,000 fold lower dose of retinoids. The current study provides a novel mechanism of retinoid action in predisposing CTCL cells to growth arrest and apoptosis by governing cell homing properties, and establishes that receptor isotype specific agonism and synergism could increase efficacy and circumvent the deleterious off-target effects commonly associated with retinoid therapies.