Effect of thyroid hormone membrane receptor inhibition in the treatment with rexinoids of Cutaneous T cell lymphoma.

VICTORIA REVUELTA; PAULAZO ALEJANDRA; CREMASCHI GRACIELA; CAYROL FLORENCIA; DIAZ FLAQUE MARIA CELESTE; CERCHIETTI LEANDRO; MERCEDES DEBERNARDI; HELENA STERLE

Mar del Plata

Congreso; LXI Reunión Científica Anual de la Sociedad. Argentina de Investigación Clínica; 2016

Cutaneous T Cell Lymphomas (CTCL) are neoplasms of mature T cells with clinical presentations from discrete skin lesions to visceral disease. CTCL are exposed to a complex paracrine and endocrine environment that influence their development. Recently we found that both nuclear (TR) and membrane (mTR, integrin V3) TH receptors regulate transcriptional programs required 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 TH replacement therapy. The consequences of TH administration on the activity of BEXA in CTCL cells are unknown. Our aim was to study the effect of TH and their genetic programs on the anti-lymphoma activity of rexinoids. To accomplish this, we perform functional assays and next generation sequencing studies in CTLC BEXA-treated cells (HuT78 and MJ) in the presence or absence of TR or mTR. Results show, that BEXA activity decrease on both, conventional or 3D CTCL cell cultures, in the presence of physiological concentrations of TH. On the other hand, in vivo assays performed on C57BL/6 mice show that CD3+ population, mainly the CD8+ cells, decrease due to BEXA-induced hypothyroidism, as TH replacement revert this effect. Considering this, we evaluated the effect in vitro of mTR inhibition in combination with BEXA treatment. We found that either, using silencing RNA or pharmacological inhibitors of mTR, the anti-lymphoma activity of BEXA increases. The improvement of BEXA activity could be explained by the increase of cell apoptosis and the inhibition of cell cycle markers. RNAseq results support the latest, showing that inhibition of mTR in cells treated with BEXA, increases the regulation of genes involved in cell cycle, apoptosis and tumorigénesis (REL, ID2, LGALS1, ZC3H12, among others). Based on our results, we proposed that mTR inhibition could be a new strategy to improve rexinoid treatment in CTCL patients.