RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect.

Retinoid X receptor () heterodimerizes with the nuclear hormone receptor and regulates its downstream events. We investigated the effects of agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. Genetic overexpression and CRISPR/Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of in -agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG100754 and lenalidomide. The combination of agonists and lenalidomide demonstrated synergistic activity in increasing expression and killing myeloma cells. Mechanistically, the agonists reduced the binding of to the promoter, thereby relieving the repressor effect of on transcription. agonists downregulated the exhaustion markers and increased the activation markers of Jurkat T cells and primary human T cells. Co-administration of LG100754 and lenalidomide showed enhanced anti-tumor activity in vivo. LG100754 retained its glucose- and lipid-lowering effects. agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.