NK cells mediate Flt3 ligand-induced protection of dendritic cell precursors in vivo from the inhibition by prostate carcinoma in the murine bone marrow metastasis model

Multiple observations suggest that suppression of the dendritic cell (DC) system might be one of the mechanisms used by the tumors to escape immune response. However, no in vivo data are available to support these in vitro observations. Here we have shown that murine prostate cancer inhibits DC generation (dendropoiesis) from the bone marrow precursors in the in vivo model in mice injected intrafemorally with RM1 prostate adenocarcinoma cells. Phenotyping of DC, generated from in vivo RM1-treated bone marrow cells, revealed a significant inhibition of dendropoiesis assessed as a percentage of CD11c+MHC11+, CD11c+CD86+, and CD11c+CD80+ cells. The stimulatory capacity of these DCs to induce T cell proliferation was also markedly decreased. Notably, Flt3 ligand-based therapy reversed the inhibitory effects of prostate cancer on dendropoiesis in vivo in wild-type and C.13-17 SCID (T and B cell deficient) mice, but not in SCID beige (T, 13, and NK cell deficient) animals, suggesting a key role of NK cells in Flt3 ligand-mediated protection of dendropoiesis from tumor-induced inhibition in vivo. Thus, these data demonstrate that prostate cancer inhibits DC hematopoietic precursors in vivo in the bone marrow and this effect could be abolished by a systemic administration of growth factor Flt3 ligand.