INVESTIGADORES
ZANETTI Flavia Adriana
congresos y reuniones científicas
Título:
THERAPEUTIC BLOCKADE OF FOXP3 IN A MURINE BREAST CANCER MODEL.
Autor/es:
MARIELA ALEJANDRA MORENO AYALA; MARIA FLORENCIA GOTTARDO; MERCEDES IMSEN; ANTONELA SOFIA ASAD; FLAVIA ZANETTI; ELISA BAL DE KIER JOFFÉ; NOELIA CASARES ; JUAN JOSE LASARTE; ADRIANA SEILICOVICH; MARIANELA CANDOLFI.
Lugar:
Mar del Plata
Reunión:
Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC), LXIV Reunión de la Sociedad Argentina de Inmunología (SAI), XLVIII Reunión Anual de la Sociedad Argentina de Farmacología Experimental (SAFE).; 2016
Resumen:
Regulatory T cells (Tregs) have been involved in the relatively low efficacy of antitumor vaccines in cancer patients. Our previous results indicate that prophylactic antitumor dendritic cell (DC) vaccines improve the survival of murine models of breast cancer.However, DC vaccines administered to tumor-bearing mice induce the expansion of Tregs and lack efficacy in this therapeutic setting. We aimed to improve the antitumor effect of DC vaccines using a cell penetrating peptide (P60) that inhibits Foxp3, a transcription factor required for Treg function. Mice bearing established LM13 or 4T1 breast tumors were treated sc with a DC vaccine loaded with tumor cell lysate and stimulated with CpG. Mice were daily treated with ip injections of P60 or a control peptide. We found that although therapeutic DC vaccines alone did not affect tumor growth, P60 alone or in combination with DC vaccines significantly reduced tumor growth rate (p˂0.05). While mono-therapy led to long-term survival in less than 70% of the animals, over 70% of mice treated with vaccine+P60 survived 100 d after tumor inoculation (p˂0.05). As we already described expression of Foxp3 in breast tumor cells, we evaluated whether the antitumor effect of P60 was an immune-mediated or a direct antitumor effect. In immuno-compromised animals bearing established tumors, we found that daily treatment with P60 for 7 d significantly delayed tumor growth doubling time C: 5 d, P60: 6 d, (p˂0.05), suggesting that Foxp3 plays a trophic role that facilitates tumor progression. However, P60 did not elicit long-term survival in these mice, suggesting that the immune-mediated effects of the treatment are required for therapeutic efficacy. Our results suggest that Foxp3 blockade could have a dual therapeutic benefit on tumor regression when used in combination with antitumor vaccines, both by inhibition of Treg function as well as through a direct antitumor effect in Foxp3-expressing tumor cells.