Inhibition of the integrin alphaVbeta3 improves the immune and anti-lymphoma effects of bexarotene in cutaneous T-cell lymphoma

DIAZ FLAQUE MARIA C; CALVO-VIDAL MN; DEBERNARDI M; CERCHIETTI LC; STERLE HA; PAULAZO ALEJANDRA; CAYROL FLORENCIA; CREMASCHI GA; PHILLIP J; REVUELTA V

Congreso; 59th ASH Annual Meeting; 2017

Bexarotene (Bex) is an oral RXR agonist that is effective for the treatment of early and advanced-stage CTCL. However, Bex is associated with the unavoidable side effect of hypothyroidism in about 95% of pts, which is prophylactically managed with the administration of thyroid hormone (TH). Paradoxically, we found (Cayrol et al, Blood 2015) that physiological levels of TH increase the proliferation of CTCL by activating both the nuclear TRA receptor and the membrane integrin V3 in these cells. Here, we determined the influence of TH replacement therapy on the anti-lymphoma activity of Bex, an unknown topic with clinical implications.Results: In standard culture conditions, Bex decreases the proliferation and viability of CTCL cell lines HuT78 and MJ. We conducted RNA-sequencing in HuT78 cells treated with Bex (vs. vehicle) to understand the mechanism/s underpinning these effects. We found that Bex regulates pathways related to ?cell proliferation and differentiation? (e.g. REL, SCD, CCND1) and ?immune system? (e.g. TBX21, IFNG, MX1), which we independently validated. This suggests that Bex treatment could also impact anti-neoplastic immunity by increasing INF-gamma release from CTCL cells. We then conducted the same experiment culturing HuT78 and MJ in TH-depleted culture conditions and observed a higher effect of Bex in decreasing proliferation and viability; supporting the notion that Bex should not be administered with TH replacement. However, hypothyroidism is associated with marked immunosuppression that could favour CTCL progression and potentially affect the immune modulator effect of Bex that we described above. We thus determined the impact of TH replacement on the anti-lymphoma effect of Bex using a murine CTCL model. We implanted murine EL4 TCL cells in the hypodermis of immunocompetent C57BL/6 mice. Once tumors developed, mice were randomized into treatment with vehicle (Veh), Bex with no TH replacement (Bex) and Bex with TH replacement (BexT4+). TH replacement was done with oral administration of T4. We measured T4 in these mice plasma by RIA to assure that mice with T4 replacement reach physiological levels and those with no T4 develop hypothyroidism. Compared to Veh mice, the administration of Bex significantly decreased lymphoma growth in both conditions although slightly better in mice without T4 replacement (p