Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma

Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the alpha V beta 3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an alpha V beta 3-dependent manner, the antineoplastic effect of bexarotene, levothyroxine supplementation in predinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin alpha V beta 3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin alpha V beta 3 inhibitors as part of CTCL regimens based on bexarotene administration. Teaser: Inhibiting alpha V beta 3 integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.

Automated summary

This study reveals the dual effects of levothyroxine in CTCL treatment. It can decrease the antineoplastic effect of bexarotene in isolated CTCL cells, but supplementation in preclinical models is necessary to avoid suppression of lymphoma immunity. Additionally, the inhibition of integrin alpha V beta 3 can enhance the antineoplastic effect of bexarotene and maintain lymphoma immunity.