Thyroid hormones regulate cell proliferation and antitumor immunity in Melanoma

Abstract

Melanoma (ME) is the most severe type of skin cancer and despiteimmune checkpoint inhibitors provide exceptionally durable responses,only a limited number of patients benefit from it, makingcrucial the study of new compounds for ME treatment. Thyroid hormones(TH) influence tumor progression by direct actions on cancercells, tumor microenvironment and antitumor immunity. Our first aimwas to evaluate TH effect on the proliferation of human (A375 andWM35) and mouse (B16F10 and B16F1) ME cells. We found thatphysiological levels of TH induce 15 to 35% ME cell proliferation(p<0.05 vs control). Moreover, cilengitide, a selective inhibitor of theTH membrane receptor (mTR) αvβ3 integrin, not only prevents theproliferative effect of TH, but also inhibits the basal viability of MEcells (*p<0.05 vs vehicle * p<0.05 vs TH). Additionally, the expressionof both integrins was found to be present on ME patient?s samplesfrom the TCGA-SKCM project, indicating that the mTR couldbe a possible target to improve ME therapy. We next evaluated theeffect of thyroid status on ME cells growing in vivo in a syngeneicmouse model. For this, C57Bl/6 mice were subcutaneously inoculatedwith B16F1 cells after the treatment with thyroxine (12mg/l,30 days) or propylthiouracil (500mg/l, 15 days) in the drinking waterto obtain hyperthyroid (hyper) and hypothyroid (hypo) mice. Hypermice showed increased tumor growth rate compared to controls andhypo mice (p<0.05). To further analyze the effect of thyroid statuson the anti-ME immune response we evaluated the distribution ofimmune subsets in secondary lymphoid organs from tumor-bearingmice. We observed an increased percentage of NK cells (p<0.05)and increased cytotoxic T lymphocyte activity (p<0.05) but also increasedproportion of MDSC (p<0.05) in spleens from hyper mice. Our results suggest that TH positively regulate ME cell proliferationthrough αvβ3 integrin and are also involved in the systemic anti-MEimmune response.