title: Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation.
abstract: In this study, we have characterized reconstitution of the natural killer (NK) cell repertoire after haploidentical CD34(+) selected hematopoietic stem cell transplantation (HSCT) for high-risk hematologic malignancies. Analysis focused on alloreactive single-KIR(+) NK cells, which reportedly are potent antileukemic effectors. One month after HSCT, CD56(bright)/CD56(dim) NK-cell subsets showed inverted ratio and phenotypic features. CD25 and CD117 down-regulation on CD56(bright), and NKG2A and CD62L up-regulation on CD56(dim), suggest sequential CD56(bright)-to-CD56(dim) NK-cell maturation in vivo. Consistently, the functional potential of these maturation intermediates against leukemic blasts was impaired. Mature receptor repertoire reconstitution took at least 3 months. Importantly, at this time point, supposedly alloreactive, single-KIR(+) NK cells were not yet fully functional. Frequency of these cells was highly variable, independently from predicted NK alloreactivity, and below 1% of NK cells in 3 of 6 alloreactive patients studied. In line with these observations, no clinical benefit of predicted NK alloreactivity was observed in the total cohort of 56 patients. Our findings unravel the kinetics, and limits, of NK-cell differentiation from purified haploidentical hematopoietic stem cells in vivo, and suggest that NK-cell antileukemic potential could be best exploited by infusion of mature single-KIR(+) NK cells selected from an alloreactive donor.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) H San Raffaele, via Olgettina 60, 20132, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Vago
authors.forename: Barbara
authors.initials: B
authors.lastname: Forno
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sormani
authors.forename: Roberto
authors.initials: R
authors.lastname: Crocchiolo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zino
authors.forename: Simona
authors.initials: S
authors.lastname: Di Terlizzi
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Lupo Stanghellini
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzi
authors.forename: Serena K
authors.initials: SK
authors.lastname: Perna
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.forename: Derek
authors.initials: D
authors.lastname: Middleton
authors.forename: Alessio
authors.initials: A
authors.lastname: Palini
authors.forename: Massimo
authors.initials: M
authors.lastname: Bernardi
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
authors.forename: Jacopo
authors.initials: J
authors.lastname: Peccatori
authors.forename: Silvano
authors.initials: S
authors.lastname: Rossini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleischhauer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis; D019002:CD56 Antigen / Q000096:biosynthesis; D002470:Cell Survival; D005260:Female; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D054340:Receptors, KIR / Q000235:genetics*; D019172:Transplantation Conditioning
chemical_list: D018952:Antigens, CD34; D019002:CD56 Antigen; D054340:Receptors, KIR