DENDRITIC CELLS (DC) MATURED WITH TRIIODOTHYRONINE (T3) IN THE PRESENCE OF TUMOR ANTIGENS INDUCE A POTENT ANTITUMORAL RESPONSE: ROLE OF T3 AS ADJUVANT IN DC-BASED CANCER VACCINES.
Alamino VA, Gigena N, Montesinos MM, Donadio AC, Milotich SI, Masini-Repiso AM, Rabinovich GA, Pellizas CG.
Background: We demonstrated that mice DC express thyroid hormone receptor β1 and that T3 stimulates DC maturation, IL-12 production and T cell allostimulatory capacity directing a T1-type response (FASEB J 2008,22:1032) involving Akt and NFkB activation signals (JBC 2010,285:9569). Moreover, T3 increased DC ability to stimulate cytotoxic antigen-specific responses and antigen cross-presentation (RAEM 2010,47:77).
Objectives: 1) to evaluate apoptosis in T3-treated DC, 2) to analyze the migratory capacity of T3-stimulated DC, 3) to assess the capacity of T3-matured DC in the presence of tumor antigen to stimulate an antitumoral response in vivo.
Methods: Mice bone marrow derived DC were pulsed with T3 (5nM) for 18 h. Apoptosis and DC migratory ability were analyzed by standard methodologies. For mice antitumor vaccination, B16-OVA melanoma model was used and immunizations with T3-pulsed DC in the presence of OVA were administered at 1, 3, 5 and 8 days after tumor cell inoculation. Tumor size was measured with vernier calipers and mice survival registered. Lymphocyte T linage was determined in tumor infiltrating cells and IFN-γ measured in esplenocytes. P<0.05 was considered significant (ANOVA-SNK, Gehan-Bislow-Wilcoxon).
Results: 1) T3 reduced DC apoptosis, 2) T3 increased DC migration to lymph nodes, 3) T3-stimulated DC-based immunotherapy was able to reduce the incidence of tumor establishment and tumor growth in affected mice, prolonging their survival. These effects were mediated, at least in part, by CD8+ T cells able to secrete IFN-γ.
Conclusions: Results strongly suggest significant adjuvant properties of T3 in DC-based tumor vaccination with profound implications in cancer immunotherapy.