This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. B7-H1 is a member of the B7 family with pleiotropic effects on T cell-mediated immune responses after ligation with its receptors. PD-1 is the identified receptor for B7-H1. We now demonstrate that a fraction of blood monocyte-derived myeloid dendritic cells (MDC) express B7-H1 on the cell surface. This expression could be upregulated by interleukin (IL)-10 and vascular endothelial cell growth factor (VEGF), two cytokines frequently associated with progressive growth of ovarian carcinomas. Consistent with this finding, virtually 100% of MDC isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blocking interaction of B7-H1 with a non-PD-1 receptor enhanced MDC-mediated stimulation of T cells, and was accompanied by a downregulation of T cell interleukin 10 (IL-10), and an upregulation of IL-2 and interferon gamma. Importantly, T cells stimulated with MDC in vitro in the presence of a B7-H1 neutralizing monoclonal antibody (mAb) had increased potency in inhibition of autologous human ovarian carcinoma growth in transplanted NOD/SCID mice. Our findings support the concept that upregulation of B7-H1 on MDC by tumor microenvironmental factors downregulates T cell anti-tumor immunity. The blockade of the B7-H1 pathway is potentially therapeutic.
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