Neuroblastoma triggers an immunoevasive program involving galectin-1-dependent modulation of T cell and dendritic cell compartments.
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.
Laboratory of Pediatric Immunotherapy, Department of Pediatrics, Medical Faculty, Otto-von Guericke University of Magdeburg, Germany.
Rocio
R
Soldati
Elisa
E
Berger
Ana C
AC
Zenclussen
Gerhard
G
Jorch
Holger N
HN
Lode
Mariana
M
Salatino
Gabriel A
GA
Rabinovich
Stefan
S
Fest
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D037483:Galectin 1 / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008805:Mice, Inbred A; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D037483:Galectin 1; D007371:Interferon-gamma