EFFECT OF THYROID HORMONE MEMBRANE RECEPTOR INHIBITION IN THE TREATMENT WITH REXINOIDS OF CUTANEOUS T CELL LYMPHOMA

CAYROL, F.; REVUELTA, V; DEBERNARDI, M; DÍAZ FLAQUÉ, M.C.; PAULAZO, M.A.; STERLE, H.A.; CERCHIETTI L; CREMASCHI, G.A.

Congreso; Reunion Anual de la Sociedad Argentina de Investigación Clinica; 2016

Cutaneous T Cell Lymphomas (CTCL) are neoplasms of matureT cells with clinical presentations from discrete skin lesionsto visceral disease. CTCL are exposed to a complex paracrineand endocrine environment that influence their development.Recently we found that both nuclear (TR) and membrane (mTR,integrin aVb3) TH receptors regulate transcriptional programsrequired for the survival and proliferation of TCL, including CTCL.For CTCL treatment the most used rexinoid, bexarotene (BEXA),is associated with hypothyroidism being patients candidate for THreplacement therapy. The consequences of TH administration onthe activity of BEXA in CTCL cells are unknown. Our aim wasto study the effect of TH and their genetic programs on the antilymphomaactivity of rexinoids. To accomplish this, we performfunctional assays andnext generation sequencing studies in CTLCBEXA-treated cells (HuT78 and MJ) inthe presence or absence ofTR or mTR. Results show, that BEXA activity decreaseon both,conventional or 3D CTCL cell cultures, in the presence ofphysiologicalconcentrations of TH. Onthe other hand, in vivo assaysperformed on C57BL/6 mice show that CD3+ population, mainlythe CD8+ cells, decrease due to BEXA-induced hypothyroidism,as TH replacement revert this effect. Considering this, we evaluatedthe effect in vitro of mTR inhibition in combination with BEXAtreatment. We found that either, using silencing RNA or pharmacologicalinhibitors of mTR, the anti-lymphoma activity of BEXAincreases. The improvement of BEXA activity could be explainedby the increase of cell apoptosis and the inhibition of cell cyclemarkers. RNAseq results support the latest, showing that inhibitionof mTR in cells treated with BEXA, increases the regulationof genes involved in cell cycle, apoptosis and tumorigénesis (REL,ID2, LGALS1, ZC3H12, among others). Based on our results, weproposed that mTR inhibition could be a new strategy to improverexinoid treatment in CTCL patients.