INHIBITION OF INTEGRIN αV3 IMPROVES REXINOID ANTITUMORAL ACTION ON CUTANEOUS T CELL LYMPHOMA (CTCL)

CAYROL F; PAULAZO A; DIAZ FLAQUE MARIA MC; CREMASCHI GA; DEBERNARDI MM; ZAMPONI N; RUAN J; REVUELTA MV; PHILLIP J; MAGRO C; CERCHIETTI LC

Congreso; 4th World Congress of Cutaneous Lymphoma; 2020

International Society of Cutaneous Lymphoma

Introduction & Objectives: Bexarotene (Bex) is an oral RXR agonist that is effective for the treatment of early and advanced-stage CTCL. However, Bex is associated with hypothyroidism in about 95% of patients, which are prophylactically managed with the administration of high doses of thyroid hormone (TH) levothyroxine. Paradoxically, we have previously found that physiological levels of TH increase the proliferation of CTCL cells by activating both the nuclear TRA and membrane integrin αVβ3 receptors. Here, we determined the influence of TH replacement therapy on the anti-lymphoma activity of Bex, an unknown topic with clinical implications.Materials & Methods: We performed in vitro and in vivo experiments with HuT78 and MJ human CTCL cells and EL4 murine cells, using RNA sequencing, RT-qPCR techniques and functional assays to determine cell viability, apoptosis and motility.Results: We found that in standard culture conditions bexarotene regulates gene and pathways related to ?cell proliferation and differentiation? (REL, CCND1) and ?immune system? (TBX21, IFNG, MX1) and ?motility and extracellular matrix interaction? (CCR7, CCR4). Bex also induce biological changes in CTCL cells that lead to a decreased cell proliferation and chemotaxis, as well an increased cell apoptosis and interferon response. Although lack of TH supplementation during bexarotene treatment significantly increased apoptosis and decreased cell proliferation of CTCL cells in vitro and in vivo, it also decreased the antitumor immune response. Since levothyroxine activates both the ubiquitous TRA nuclear receptor and the integrin αVβ3 membrane receptor that is overexpressed in CTCL cells, we investigated their role in bexarotene treatment. We demonstrated that genetic and pharmacologic inhibition of the integrin αVβ3 receptor resulted in improved bexarotene-induced effects on apoptosis, cell proliferation and chemotaxis while maintaining the antitumor immunity.