Naive Donor NK Cell Repertoires Associated with Less Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Acute and latent human CMV cause profound changes in the NK cell repertoire, with expansion and differentiation of educated NK cells expressing self-specific inhibitory killer cell Ig-like receptors. In this study, we addressed whether such CMV-induced imprints on the donor NK cell repertoire influenced the outcome of allogeneic stem cell transplantation. Hierarchical clustering of high-resolution immunophenotyping data covering key NK cell parameters, including frequencies of CD56bright, NKG2A+, NKG2C+, and CD57+ NK cell subsets, as well as the size of the educated NK cell subset, was linked to clinical outcomes. Clusters defining naive (NKG2A+CD57−NKG2C−) NK cell repertoires in the donor were associated with decreased risk for relapse in recipients with acute myeloid leukemia and myelodysplastic syndrome (hazard ratio [HR], 0.09; 95% confidence interval [CI]: 0.03–0.27; p < 0.001). Furthermore, recipients with naive repertoires at 9–12 mo after hematopoietic stem cell transplantation had increased disease-free survival (HR, 7.2; 95% CI: 1.6–33; p = 0.01) and increased overall survival (HR, 9.3; 95% CI: 1.1–77, p = 0.04). Conversely, patients with a relative increase in differentiated NK cells at 9–12 mo displayed a higher rate of late relapses (HR, 8.41; 95% CI: 6.7–11; p = 0.02), reduced disease-free survival (HR, 0.12; 95% CI: 0.12–0.74; p = 0.02), and reduced overall survival (HR, 0.07; 95% CI: 0.01–0.69; p = 0.02). Thus, our data suggest that naive donor NK cell repertoires are associated with protection against leukemia relapse after allogeneic HSCT.

The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease

“…Importantly, while NK cell alloreactivity in HLA-mismatched alloSCT can prevent GvHD, this alloreactivity is fundamental to achieving a significant antileukemic response. There are recent studies indicating an association of specific NK repertoires with less leukemia relapses after alloSCT [19,20]. Due to the very limited number of patients experiencing a relapse—One patient had a relapse within the first year after alloSCT and two additional patients relapsed after our observation period of one year—we could not establish a relationship between NKG2C expression and antileukemic response.…”

Cytomegalovirus: an unlikely ally in the fight against blood cancers?

“…Interestingly, in a smaller prospective study of 106 allogeneic HSCT patients afflicted with a variety of haematological malignancies (including 37 patients with AML, 21 with MDS and 12 with CLL), Bjorklund et al . reported a protective effect of the naive NK cell repertoire (defined as NKG2C neg /NKG2A pos /CD57 neg ) on leukaemic relapse. This study directly contradicts the findings of Cichocki et al .…”

Harnessing NK Cell Memory for Cancer Immunotherapy

“…Miller and colleagues recently observed increased frequency and numbers of HCMV-adaptive NK cells in patients with HCMV reactivation, with a trend toward lower leukemia early relapse rates [44]. In a separate study, Malmberg and colleagues observed lower leukemia relapse rates in patients who had higher frequencies of “naïve” (NKG2C - CD57 - NKG2A + ) NK cells following allogeneic HCT when assessed at later time points [49]. These contrasting results highlight the complexity of correlating NK cell phenotype with outcomes in the context of HCT, and may reflect differences in conditioning regimens, stem cell source, KIR-HLA mismatch, and time points chosen for NK cell assessment.…”