Dendritic cells (DC) pulsed with thyroid hormone in the presence of tumor antigens induce a potent antitumor response: role of triiodothyronine as adjuvant in DC-based cancer vaccines.

ALAMINO VA; GIGENA N; MONTESINOS MM; DONADIO AC; MILOTICH S; MASINI-REPISO AM; RABINOVICH GA; PELLIZAS CG.

San Francisco

Congreso; The Endocrine Society’s 95th annual meeting and expo.; 2013

The Endocrine Society

We demonstrated that mice dendritic cells (DC), the main antigen (Ag)-presenting cells, express thyroid hormone receptor (TR) β1 and that physiological levels of triiodothyronine (T3) stimulate the maturation of DC and IL-12 production. Furthermore, T3-stimulated DC increased the T cell allostimulatory capacity directing a T1-type response1 involving PI3K-independent, Akt and NFkB activation signals2. Moreover, T3 increased DC ability to stimulate a cytotoxic Ag-specific response in vivo and an Ag cross-presentation in vitro3. Recently, there has been a growing interest in the application of cancer therapies based on the immunization of patients with their own DC loaded with tumor-associated Ag ex vivo as an alternative to radiotherapy and chemotherapy for malignant tumors treatment4. However, the clinical success of DC-based immunotherapy is limited needing optimization. Considering our previous findings, we hypothesized that T3 could be a powerful adjuvant in DC-based antitumor vaccination. 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 Ag to stimulate an anti-tumor immune 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 the immunotherapy consisted of four immunizations with T3-pulsed DC in the presence of OVA at 1, 3, 5 and 8 days after tumor cell inoculation. Tumors were measured with vernier calipers and animal survival was defined as the time in days between tumor cell inoculation and the day of sacrifice (tumor diameter: 2cm). P<0.05 was considered statistically significant (ANOVA, Student-Neuman-Keuls, Gehan-Bislow-Wilcoxon). Results: 1) T3 reduced DC apoptosis, 2) T3 induced 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 registered antitumor effects were mediated, at least in part, by CD8+ T cells (induced by the ability of T3 to generate a Th1 profile) capable of secreting large amounts of IFN-γ. Conclusions: Our results strongly suggest significant adjuvant properties of T3 in DC-based antitumor vaccination with profound implications in cancer immunotherapy.