Tumors promote altered maturation and early apoptosis of monocyte-derived dendritic cells.

Sylvia M Kiertscher,Michael D Roth,Jie Luo,Steven M Dubinett

doi:10.4049/jimmunol.164.3.1269

Abstract

Tumors produce a number of immunosuppressive factors that block the maturation of CD34+ stem cells into dendritic cells (DC). We hypothesized that tumors might also interfere with the maturation and/or function of human monocyte-derived DC. In contrast to stem cells, we found that CD14+ cells responded to tumor culture supernatant (TSN) by increasing expression of APC surface markers, up-regulating nuclear translocation of RelB, and developing allostimulatory activity. Although displaying these characteristics of mature DC, TSN-exposed DC lacked the capacity to produce IL-12, did not acquire full allostimulatory activity, and rapidly underwent apoptosis. The effects of TSN appeared to be specific for maturing DC, and were not reversed by Abs against known DC regulatory factors including IL-10, vascular endothelial growth factor, TGF-beta, or PGE2. Supernatants collected from nonmalignant cell sources had no effect on DC maturation. The altered maturation and early apoptosis of monocyte-derived DC may represent another mechanism by which tumors evade immune detection.

Highlights

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A marker expressed on both immature and mature dendritic cells (DC), CD11c, was reduced in cells cultured with tumor culture supernatant (TSN), while the same cells expressed higher than control levels of CD83, a marker of more mature DC
APC marker expression remained relatively constant (CD86, 6637 vs 6108 linear fluorescence intensity (LFI); HLA-DR, 4752 vs 4990 LFI) or significantly decreased (CD80, 2137 vs 1290 LFI; CD40, 1101 vs 715 LFI; CD83, 433 vs 102 LFI; CD11c, 2642 vs 910 LFI) on DC grown in the presence of TSN

Summary

Abbreviations used in this paper

DC, dendritic cells; LFI, linear fluorescence intensity; TSN, tumor supernatant; VEGF, vascular endothelial growth factor; CD40L, CD40 ligand. In contrast to the responses reported for CD34ϩ precursors, DC generated from monocytes in the presence of TSN appeared mature, expressing essential cell surface molecules, enhanced translocation of RelB to the nucleus, and early development of T cell stimulatory activity. These cells did not develop full allostimulatory activity, had a diminished capacity to produce IL-12 and IL-10, and rapidly underwent apoptosis following this early, defective maturation process. While mediated by different mechanisms, TSN appears to effectively suppress the function of both monocyte- and stem cell-derived DC

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Discussion