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.
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.
Vago
Luca
L
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.
Forno
Barbara
B
Sormani
Maria Pia
MP
Crocchiolo
Roberto
R
Zino
Elisabetta
E
Di Terlizzi
Simona
S
Lupo Stanghellini
Maria Teresa
MT
Mazzi
Benedetta
B
Perna
Serena K
SK
Bondanza
Attilio
A
Middleton
Derek
D
Palini
Alessio
A
Bernardi
Massimo
M
Bacchetta
Rosa
R
Peccatori
Jacopo
J
Rossini
Silvano
S
Roncarolo
Maria Grazia
MG
Bordignon
Claudio
C
Bonini
Chiara
C
Ciceri
Fabio
F
Fleischhauer
Katharina
K
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
D018952:Antigens, CD34; D019002:CD56 Antigen; D054340:Receptors, KIR