INVESTIGADORES
RABINOVICH Gabriel Adrian
artículos
Título:
NEUROBLASTOMA TRIGGERS AN IMMUNOEVASIVE PROGRAM INVOLVING GALECTIN-1-DEPENDENT MODULATION OF T CELL AND DENDRITIC CELL COMPARTMENTS
Autor/es:
SOLDATI R; BERGER E; ZENCLUSSEN AC; JORCH G; LODE HN; SALATINO M; RABINOVICH GA; FEST S
Revista:
INTERNATIONAL JOURNAL OF CANCER. JOURNAL INTERNATIONAL DU CANCER.
Editorial:
JOHN WILEY & SONS INC
Referencias:
Lugar: Munich; Año: 2012 vol. 131 p. 1131 - 1141
ISSN:
0020-7136
Resumen:
The immunosuppressive strategies devised by neuroblastoma (NB), the most common solid extracranial childhood cancer, are poorly understood. Here, we identified an immunoevasive program triggered by NB through secretion of galectin-1 (Gal-1), a multifunctional glycan-binding protein. Human and mouse NB cells express and secrete Gal-1, which negatively regulates T cell and dendritic cell function. When injected subcutaneously in syngeneic A/J mice, knockdown transfectants expressing low amounts of Gal-1 (NXS2/L) showed reduction of primary tumor growth by 83–90% and prevented spontaneous liver metastases in contrast to NXS2 cell variants (NXS2/H, NXS2 wildtype) expressing high amounts of Gal-1. Splenocytes from mice receiving Gal-1 knockdown NXS2/L cells secreted higher amounts of IFN-γ and displayed enhanced cytotoxic T-cell function compared to NXS2/H or NXS2 controls. Immunohistochemical analysis revealed a six- to tenfold increase in the frequency of CD4+ and CD8+ T cells infiltrating tumors from mice receiving knockdown transfectants. This effect was confirmed by in vitro migration assays. Finally, supernatants of NXS2/H or NXS2 cells suppressed dendritic cell (DC) maturation and induce T cell apoptosis, whereas these effects were only marginal on DCs and T cells exposed to supernatants from NXS2/L cells. These results demonstrate a novel immunoinhibitory role of the Gal-1-glycan axis in NB, highlighting an alternative target for novel immunotherapeutic modalities.