IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Unveiling antigens in a non-immunogenic spontaneous murine tumor using a dendritic cell-based vaccine
Autor/es:
P. CHIARELLA; V. REFFO; J. BRUZZO; R.A. RUGGIERO
Lugar:
Berlín, Alemania
Reunión:
Congreso; 2nd European Congress of Immunology. Berlin, Alemania. 13-16 de Septiembre 2009.; 2009
Resumen:
Most attempts to use immunotherapy to cause the regression of animal and human established tumors have not been successful. Former experiments have suggested that this failure could be related, at least in part, to a lack of immunogenicity of spontaneous tumors. In this work, we have investigated whether this lack of immunogenicity can be attributed to the absence of tumor antigens or to the existence of tolerogenic mechanisms preventing such antigens from initiating an antitumor immune response. Material and methods: Tumors: a non-immunogenic spontaneous lymphoma (LB) and a strongly immunogenic methylcholanthrene-induced fibrosarcoma (MC-C). Immunization assays: Dendritic cells (DC) loaded in vitro with tumor lysate and then inoculated in the foot pad of mice. Results: When DC were pulsed with LB lysate (DC + LB), no maturation of DC was achieved in vitro and no protection against LB implants after DC + LB inoculation was observed in vivo. On the other hand, when DC were pulsed with MC-C lysate (DC + MC-C), maturation of DC was observed along with a strong protection against MC-C implants after DC +MC-C inoculation. Finally, when DC were pulsed with both LB and MC-C lysates (DC + LB + MC-C), a mild maturation of DC was observed together with a slight but significant protection against LB and a significant reduction of the protection against MC-C. Since no immune cross reaction between LB and MC-C was ever observed, the results presented herein suggest: 1) that LB bears specific tumor antigens but lacks other signals to achieve DC maturation; these signals could be provided, at least in part, by MC-C, 2) that LB displays active tolerogenic mechanisms which reduce the protection against MC-C when DC + LB + MC-C are inoculated in vivo and presumably also is responsible for the absence of madurative signals for DC in the LB lysate. These tolerogenic mechanisms seem to be associated with a high expression of STAT3 in LB cells, since inhibition of STAT3 by treating LB tumor- bearing mice with the specific inhibitor cucurbitacin, improved the ability of LB tumor lysate to promote the maturation of DC. The expression of STAT3 in MC-C cells was, on the other hand, always very low. We propose that the high expression of STAT3 is one of the reasons by which the spontaneous LB tumor behaves as a non-immunogenic, and that targeting that expression might promote an efficient antitumor immune response against this spontaneous tumor.