Selective expansion of human natural killer cells leads to enhanced alloreactivity

Abstract

In allogeneic stem cell transplantation (SCT), natural killer (NK) cells lacking their cognate inhibitory ligand can induce graft-versus-leukemia responses, without the induction of severe graft-versus-host disease (GVHD). This feature can be exploited for cellular immunotherapy. In this study, we examined selective expansion of NK cell subsets expressing distinct killer immunoglobulin-like receptors (KIRs) within the whole human peripheral blood NK cell population, in the presence of HLA-Cw3 (C1) or Cw4 (C2) transfected K562 stimulator cells. Coculture of KIR 1 NK cells with C1 or C2 positive K562 cells, in the presence of IL-21IL-15, triggered the outgrowth of NK cells that missed their cognate ligand. This resulted in an increased frequency of alloreactive KIR 1 NK cells within the whole NK cell population. Also, after preculture with K562 cells lacking their cognate ligand, we observed that this alloreactive NK population revealed higher numbers of CD107 1 cells when cocultured with the relevant K562 HLA-C transfected target cells, as compared to coculture with untransfected K562 cells. This enhanced reactivity was confirmed using primary leukemic cells as target. This study demonstrates that HLA class I expression can mediate the skewing of the NK cell repertoire and enrich the population for cells with enhanced alloreactivity towards leukemic target cells. This feature may support future clinical applications of NK cell-based immunotherapy.

Peripheral Blood Stem Cell Mobilization in Healthy Donors by Granulocyte Colony-Stimulating Factor Causes Preferential Mobilization of Lymphocyte Subsets

“…We did not find any associations between the infused dose of various immune cell subsets and the clinical outcome of the recipients, and results from previous studies of associations between cell subset dose and outcome are also conflicting ( 29 , 30 , 33 , 48 – 50 ). Our present results support previous studies suggesting that the balance between different immunocompetent cell subsets is important ( 31 , 32 , 37 , 51 ) and in addition our results suggest that the broader immunocompetent cell subset profile as well as the dose-independent responsiveness to G-CSF (i.e., the increase in the concentrations of various subsets, Figure 4 ) are more important than differences in single cell subset levels.…”

Immune Reconstitution-Based Score for Risk Stratification of Chronic Graft-Versus-Host Disease Patients

“…-NK cells were found to have a negative prognostic implication when lower than 115 cells/mm 3 . This finding points to the protective effect that NK cells have in cGvHD pathophysiology; it was demonstrated (42) that NK cells mediate the reduction of GvHD by inhibiting activated, alloreactive T cells while retaining graft-versus-tumor effects through effector molecules such as FasL (43). Thus, similarly to T cells, NK cells display a potent anti-leukemia effector capacity, and yet, unlike them, do not mediate cGvHD (44).…”

A novel method to expand large numbers of CD56+ natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation

“…Differences in the starting population and in culture methods used to expand cells likely account for why more phenotypically mature NK cells were expanded using our system. Several groups have investigated the functional properties of expanded UCB NK cell populations 41,42 . Prior studies have shown that UCB derived CD56 + cells have low cytotoxic activity compared to their peripheral blood counterparts 43 , however their function can be augmented by IL-2 or IL-15.…”