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

Abstract

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+MHCII+, 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.B-17 SCID (T and B cell deficient) mice, but not in SCID beige (T, B, 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.

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: Utilization for ovarian cancer treatment

“…Previous reports suggested the risk that systemically administered FLT3L could induce immunotolerance in vivo by increasing immature DCs (17)(18)(19)(20)(21), although others reported contrary findings (4,15). These conflicting data suggest that FLT3L may give rise to immunotolerance if administered systemically, and the enhancement of tumor immunity mainly depends on the circumstances where local immune response is evoked.…”

“…To date, the function of FLT3L has mainly been examined in hematopoietic progenitor cells, as FLT3 is expressed almost exclusively in hematopoietic progenitor cells (8)(9)(10)(11). FLT3L is known to cause proliferation of hematopoietic stem cells in vitro (12,13) and as a result, systemic administration of soluble FLT3L, which increases circulating numbers of dendritic cells (DCs) and natural killer (NK) cells, enhances anti-tumoral and viral immunity in vivo (3,(14)(15)(16). However, systemic FLT3L administration may also cause tolerance because of the increased number of immature DCs (17)(18)(19)(20).…”

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition

“…Herein, we describe the use of a cell line derived from the MPR model, the RM1 cell line, as a potentially effective model for investigating prostate cancer:bone stromal interactions in immune competent mice. To our knowledge, the introduction of RM1 cells into bone has been limited to studies investigating prostate cancer regulation of dendritic cell formation [15,16].…”

Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine

“…Previous reports also indicated that Flt3L protein can induce DC differentiation and NK-cell activation. [27][28][29] We therefore isolated splenocytes and assessed their NK-cell activity against YAC-1 target cells. 28 Mice vaccinated with pN-neu combined with pFLAG or with pFL/pGM induced higher levels of NK-cell activity than mice vaccinated with either pN-neu plus control vector or saline did (Figure 7c).…”