title: 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 CD56(bright), 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.
authors.affiliation: Department of Hematology, Karolinska University Hospital, 14186 Stockholm, Sweden; Center for Infectious Medicine, Karolinska Institutet, 14186 Stockholm, Sweden;
authors.forename: Andreas T
authors.identifier: http://orcid.org/0000-0001-7515-2971
authors.initials: AT
authors.lastname: Björklund
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway;
authors.forename: Trevor
authors.identifier: http://orcid.org/0000-0001-9896-0613
authors.initials: T
authors.lastname: Clancy
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway;
authors.forename: Jodie P
authors.initials: JP
authors.lastname: Goodridge
authors.affiliation: Center for Infectious Medicine, Karolinska Institutet, 14186 Stockholm, Sweden;
authors.forename: Vivien
authors.initials: V
authors.lastname: Béziat
authors.affiliation: Center for Infectious Medicine, Karolinska Institutet, 14186 Stockholm, Sweden;
authors.forename: Marie
authors.initials: M
authors.lastname: Schaffer
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway; Institute of Cancer Genetics and Informatics, Oslo University Hospital, 3010 Oslo, Norway; Department of Informatics, University of Oslo, 0316 Oslo, Norway; and.
authors.forename: Eivind
authors.initials: E
authors.lastname: Hovig
authors.affiliation: Center for Infectious Medicine, Karolinska Institutet, 14186 Stockholm, Sweden;
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
authors.affiliation: Department of Hematology, Karolinska University Hospital, 14186 Stockholm, Sweden;
authors.forename: Per T
authors.initials: PT
authors.lastname: Ljungman
authors.affiliation: Department of Hematology, Karolinska University Hospital, 14186 Stockholm, Sweden; Center for Infectious Medicine, Karolinska Institutet, 14186 Stockholm, Sweden; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway kalle.malmberg@ki.se.
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Malmberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts / Q000276:immunology*; D002648:Child; D016000:Cluster Analysis; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology*; D007938:Leukemia / Q000276:immunology* / Q000401:mortality / Q000601:surgery; D016131:Lymphocyte Subsets / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D014019:Tissue Donors; D055815:Young Adult