PURPOSE:

tumor-associated TIE-2-expressing monocytes (TEM) are highly pro-angiogenic cells critical for tumor vascularization. We previously showed that in human breast cancer TIE-2 and VEGFR pathways control TEM pro-angiogenic activity. Here, we examine the contribution of these pathways to TEM immunosuppressive activity.

EXPERIMENTAL DESIGN:

we investigated the changes in TEM immunosuppressive activity and gene expression in response to specifickinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEM to suppress tumor-specific T cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was performed using confocal microscopy images analysis of breast carcinomas.

RESULTS:

TEM from breast tumors are able to suppress tumor-specific immune responses. Importantly, TEM pro-angiogenic and suppressive function are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEM can function as antigen presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEM to change their phenotype into cells with features of myeloid dendritic cells. We demonstrate that TEM immunosuppressive activity is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells.

CONCLUSIONS:

these results suggest that TEM are plastic cells that can be reverted from suppressive, pro-angiogenic cells, into cells that are able to mediate an anti-tumoral immune response.

PMID:

 23649001