ANTITUMOR IMMUNE RESPONSES GENERATED BY TRIIODOTHYRONINE (T3)-STIMULATED DENDRITIC CELLS (DCS) LOADED WITH TUMOR-SPECIFIC ANTIGENS IN A MURINE COLON CANCER MODEL. ROLE OF T3 IN HUMAN DCS

SOLER MF; NEGRETTI-BORGA D; BRAVO-MIANA R; DONADIO, AC; PELLIZAS CG; MONTESINOS, MM

Chicago

Congreso; 89th Annual Meeting of the American Thyroid Association; 2019

We reported that mice DCs, the main antigen (Ag)-presenting cells, express thyroid hormone receptor and that T3 stimulates the maturation of DCs and their ability to direct adaptive responses towards a Th1- and Th17-type profiles, as well as cytotoxic and antitumor effects. Given their potential to stimulate adaptive antitumor immune responses, tumor Ag?loaded DCs have come in recent years as pharmacological tools for cancer immunotherapy. However, methods of vaccine preparation deserve optimization since tumor cell cargo and DC functional state induced by maturation signals influence their in vivo immunogenic potential. Objectives: 1) to analyze the antitumor potential directed by T3-stimulated DCs loaded with tumor Ags in a colon cancer murine model; 2) to assess the effect of T3 on human DCs (hDCs) for future translation to oncotherapeutics.Colon cancer MC38 cells were UV-irradiated to induce apoptotic and necrotic cells (A/N-MC38). Immature DCs (iDCs) or T3-stimulated DCs (5nM for 18h, T3-DCs) were incubated with A/N-MC38. DC?s intracellular and secreted IL-12 production were assayed by FACS and ELISA. MC38 cells were sc injected to C57BL/6 mice (day 0). iDCs or T3-DCs pulsed with A/N-MC38 were sc injected at days 1, 3, 5, 7 after tumor cell inoculation and tumor volume was measured. Lymphocyte linages in tumor-draining lymph nodes and spleen were determined (FACS). hDCs were pulsed with T3 (5nM for 18h), and surface phenotype and IL-12 production were analysed by FACS. Statistics:ANOVA-SNK,p<0.05.1a)T3-DCs cultured with A/N-MC38 cells produced higher amount of IL-12 than iDCs. 1b)Tumor-bearing mice immunized with T3-DCs loaded with tumor-Ags showed an inhibition in tumor growth. 1c)Mice receiving T3-DCs-Ag showed an increase in proinflammatory and Ags specific cytotoxic lymphocytes, as well as a decrease in T regulatory cells in spleen and lymph nodes. 2)T3 induces phenotypic and functional activation of hDCs, with an increase in CD86 expression and IL-12 production.These results suggest that T3 endows mice DCs with enhanced ability to potentiate a specific T-cell-mediated antitumor immunity. Furthermore, our findings in hDCs support promising advances in the translation process to human oncotherapy.