Blood Dendritic Cells Suppress NK Cell Function and Increase the Risk of Leukemia Relapse after Hematopoietic Cell Transplantation

Abstract

NK cells play an important role in hematopoietic stem cell transplantation (HCT) and in cross talk with dendritic cells (DCs) to induce primary T cell response against infection. Therefore, we hypothesized that blood DCs should augment NK cell function and reduce the risk of leukemia relapse after HCT. To test this hypothesis, we conducted laboratory and clinical studies in parallel. We found that although phenotypically NK cells could induce DC maturation and DCs could in turn increase activating marker expression on NK cells, paradoxically, both BDCA1+ myeloid DCs and BDCA4+ plasmacytoid DCs suppressed the function of NK cells. Patients who received an HLA-haploidentical graft containing larger number of BDCA1+ DCs or BDCA4+ DCs had a higher risk of leukemia relapse and poorer survival. Further experiments indicated that the potent inhibition on NK cell cytokine production and cytotoxicity was mediated in part through the secretion of IL-10 by BDCA1+ DCs and IL-6 by BDCA4+ DCs. These results have significant implications for future HCT strategies.

Immune reconstitution after hematopoietic cell transplantation

“…Unfortunately, large numbers of PDCs may also inhibit GVL [55,56]. Host dendritic cells are relatively chemoresistant/radioresistant; they play a significant role in GVHD as they activate alloantigen-specific donor T cells.…”

“…All these complications are due at least in part to immune deficiency or dysregulation. Here we review how various components of the immune system recover (summarized in Table 1 [1][2][3][4][5][6][7]8 & , [9][10][11][12][13][14][15][16][17][18][19][20][21][22], [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72]). Additional in depth reviews on immune reconstitution can be found elsewhere [21,[72][73][74][75].…”

Early evaluation of immune reconstitution following allogeneic CD3/CD19-depleted grafts from alternative donors in childhood acute leukemia

“…Previous studies have shown that a high donor DC content in the graft may increase leukemia relapse because of the suppressive effects on NK cells through IL-6 and IL1-10, but fast DC recovery in the recipients may increase survival by reducing infections. 28 Unfortunately, in our RIC setting, we did not determine the chimerism status among DCs because of the small amount of cells available. Nevertheless, post HSCT infusion of non-alloreactive T cells and DCs could be a strategy to minimize infection post HSCT.…”

Infusions of Allogeneic Natural Killer Cells as Cancer Therapy

“…After separation, the product typically contains more than 90% NK cells with very few T cells, B cells, and monocytes. Thus, the risks of GVHD, regulatory T cell (Treg) suppression, cytokine competition, Epstein-Barr virus-lymphoproliferative disease, passenger lymphocyte syndrome, cytokine storm, and suppression by myeloid suppressor cells or blood DCs are minimized (38)(39)(40). The NK phenotype is unaltered, and cells retain extensive proliferative capacity in vivo with potent antitumor response (41).…”