Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia
Abstract
:1. Introduction
2. Results
2.1. Criteria for Donor Selection
2.1.1. Advantage of NK Alloreactivity in the Anti-Leukemia Effect
2.1.2. Relevance of Activating NK Cell Receptors
2.2. Infused NK Cells Persist and Are Functional up to One-Month Post-Transplant
2.3. Analysis of NK Alloreactivity in the Reconstituted Repertoire after Transplantation
2.3.1. Dynamics of the Alloreactive NK Cell Subset
2.3.2. Influence of HCMV Reactivation on Alloreactive NK-Cell Phenotype
2.3.3. Anti-Leukemia Activity
2.4. Evaluation of Differentiated vs. Naïve NK-Cell Repertoires and Possible Correlation with the Clinical Outcome
3. Discussion
4. Materials and Methods
4.1. Patients and Donors
4.2. KIR, KIR-Ligand, and NKG2C Analyses
4.3. NK Cell Phenotype of Donors and Post-Transplant Patients
4.4. Leukemia Cells
4.5. Functional Assays
4.6. Unsupervised Hierarchical Cluster Analysis
4.7. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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ALLO * | UPN | Diagnosis | Donor | HCMV Serology D/R | NKG2C | B cont | Permissive iKIR * | aKIR (2DS1, 2DS2) # | Viral Infections ∞ | Acute GvHD | Relapse/TRM | Alive | Infused NK Cells (×106/kg) § | Alloreactive Subset ‡ | Cluster Phenotype ¶ | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Donor | Recipient Post-1M | Recipient Post-3/6M | Donor | Recipient | ||||||||||||||
C1 | 1 | AML (M4) | Father | neg/pos | ORF/ORF | 2 | 2DL2/L3 | 2DS1,2DS2 | HCMV | NO | NO | YES | 33.9 | 5 | 2 | 8 | Naive | Naive |
2 | T-ALL | Mother | pos/pos | ORF/ORF | 1 | 2DL2/L3 | 2DS2 | HCMV | NO | NO | YES | 82.83 | 13 | 7 | 21 | Naive | Adaptive | |
6 | BCP-ALL | Father | neg/pos | ORF/ORF | 1 | 2DL3 | 2DS1 | NO | NO | Relapse | NO | 75.3 | 12 | 5 | 18 | nd | nd | |
7 | BCP-ALL | Mother | neg/pos | ORF/ORF | 1 | 2DL3 | 2DS1 | HCMV | NO | NO | YES | 65.95 | 17 | nd | 22 | nd | Adaptive | |
10 | BCP-ALL | Mother | pos/pos | ORF/ORF | 1 | 2DL2/L3 | 2DS2 | BK | NO | NO | YES | 94.76 | 9 | nd | 5 | Adaptive | Adaptive | |
22 | BCP-ALL | Father | pos/pos | ORF/ORF | 1 | 2DL2/L3 | 2DS2 | NO | Grade II | NO | YES | 22.4 | 8 | 4 | 5 | Naive | Adaptive | |
29 | AML (M1) | Father | pos/neg | ORF/delta | 3 | 2DL2/L3 | 2DS1,2DS2 | NO | NO | NO | YES | 22.6 | 14 | 2 | 9 | Naive | Naive | |
35 | T-ALL | Mother | pos/neg | ORF/ORF | 2 | 2DL2 | 2DS2 | NO | Grade I | Relapse | NO | 16.4 | 23 | 2 | 6 | Naive | Naive | |
40 | T-ALL | Father | pos/pos | delta/delta | 0 | 2DL3 | NO | NO | NO | NO | YES | 13.4 | 33 | 10 | 8 | NA | NA | |
45 | AML (M7) | Mother | pos/pos | ORF/ORF | 1 | 2DL3 | 2DS1 | HCMV, ADV | NO | Relapse | NO | 56.1 | 20 | 25 | NA | Naive | NA | |
38 | AML (M4) | Mother | pos/pos | ORF/ORF | 0 | 2DL3 | NO | HCMV, VRS | NO | NO | YES | 23.3 | 15 | 15 | 16 | nd | Adaptive | |
73 | B-ALL | Father | pos/pos | ORF/delta | 3 | 2DL2/L3 | 2DS1,2DS2 | HHV6 | Grade II | TRM | NO | 30 | 20 | nd | NA | Naive | NA | |
75 | AML (M7) | Father | pos/pos | ORF/ORF | 1 | 2DL2/L3 | 2DS2 | NO | NO | Relapse | NO | 57.5 | 5 | 0 | 1 | Adaptive | Naive | |
5 | T-ALL | Father | pos/pos | ORF/ORF | 2 | 2DL2/L3, 3DL1 | 2DS1 | BK | NO | NO | YES | 86.6 | 13 | 4 | 9 | Naive | Naive | |
64 | B-ALL | Mother | pos/pos | ORF/delta | 2 | 2DL3, 3DL1 | 2DS1,2DS2 | HCMV, BK | NO | Relapse | NO | 57.6 | 6 | 4 | 4 | Naive | Naive | |
C2 | 4 | BCP-ALL | Mother | pos/neg | ORF/ORF | 0 | 2DL1 | NO | NO | NO | NO | YES | 53.9 | 5 | 1 | 1 | nd | Naive |
18 | BCP-ALL | Father | pos/pos | ORF/ORF | 1 | 2DL1 | 2DS1 | NO | NO | NO | YES | 87.9 | 19 | 6 | 7 | Naive | Naive | |
23 | BCP-ALL | Mother | pos/pos | ORF/delta | 0 | 2DL1 | NO | HCMV | Grade II | NO | YES | 16.7 | 13 | 5 | 3 | Naive | Naive | |
24 | AML (M2) | Father | pos/pos | ORF/ORF | 2 | 2DL1 | 2DS1,2DS2 | BK | NO | Relapse | NO | 66.7 | (7) | (15) | (22) | nd | nd | |
27 | AML (M0) | Mother | neg/neg | ORF/ORF | 1 | 2DL1 | 2DS2 | NO | NO | Relapse | NO | 21.5 | (9) | (1.6) | (2) | Naive | Naive | |
30 | BCP-ALL | Mother | pos/pos | ORF/ORF | 0 | 2DL1 | NO | NO | Grade I | NO | YES | 13.6 | 6 | 0.7 | 1 | Naive | Naive | |
39 | BCP-ALL | Father | pos/neg | ORF/delta | 3 | 2DL1 | 2DS1,2DS2 | NO | NO | NO | YES | 60.2 | (4) | (2.5) | (5) | Naive | Adaptive | |
43 | AML (M4) | Father | pos/pos | ORF/delta | 0 | 2DL1 | NO | HCMV | NO | NO | YES | 54.1 | 47 | 4 | 5 | Adaptive | Naive | |
50 | AML (M4) | Father | pos/pos | ORF/delta | 3 | 2DL1 | 2DS1,2DS2 | NO | NO | NO | YES | 6.8 | (5) | (0) | (1) | Naive | Naive | |
58 | AML (M5) | Father | pos/pos | ORF/delta | 1 | 2DL1 | 2DS2 | NO | Grade II | NO | YES | 31.2 | (22) | (5) | (6) | Adaptive | Adaptive | |
61 | B-ALL | Mother | pos/pos | ORF/ORF | 1 | 2DL1 | 2DS2 | H1N1 | NO | NO | YES | 51.67 | (25) | (7) | (9) | Adaptive | Adaptive | |
66 | T-ALL | Mother | pos/pos | ORF/ORF | 3 | 2DL1 | 2DS1,2DS2 | HHV6 | Grade I | NO | YES | 12.77 | (8) | (3) | (2) | Naive | Naive | |
71 | BCP-ALL | Mother | pos/pos | ORF/ORF | 1 | 2DL1 | 2DS2 | HCMV, HHV6 | NO | NO | YES | 12.4 | (8) | nd | (1) | Adaptive | Adaptive | |
79 | AML (M4) | Mother | pos/neg | ORF/ORF | 0 | 2DL1 | NO | NO | NO | NO | YES | 28.3 | 6 | 1 | nd | Naive | nd | |
Bw4 | 12 | BCP-ALL | Mother | pos/pos | ORF/ORF | 1 | 3DL1 | 2DS2 | HCMV | Grade II | NO | YES | 90.2 | (15) | (2) | (2) | Naive | Adaptive |
26 | BCP-ALL | Father | pos/pos | ORF/ORF | 2 | 3DL1 | 2DS2 | HCMV | NO | Relapse | NO | 35 | (3) | (2) | (2) | Adaptive | Adaptive | |
20 | AML (M3) | Mother | pos/pos | ORF/delta | 3 | 3DL1 | 2DS1,2DS2 | NO | NO | NO | YES | 82.3 | (6) | nd | (2) | Naive | Naive | |
21 | BCP-ALL | Mother | pos/pos | ORF/ORF | 2 | 3DL1 | 2DS1,2DS2 | NO | NO | NO | YES | 36.5 | (3) | nd | (2) | Naive | Naive | |
47 | ALL-bifen | Mother | pos/pos | ORF/ORF | 0 | 3DL1 | NO | NO | NO | NO | YES | 7.87 | 2 | 1 | 1 | Naive | Naive | |
51 | T-ALL | Mother | pos/neg | ORF/ORF | 0 | 3DL1 | NO | NO | NO | NO | YES | 44.7 | 10 | 2 | 7 | Adaptive | Naive | |
72 | T-ALL | Father | pos/pos | ORF/delta | 2 | 3DL1 | 2DS1,2DS2 | ADV | Grade II | NO | YES | 82.6 | (2) | nd | (2) | Naive | Naive |
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Meazza, R.; Falco, M.; Loiacono, F.; Canevali, P.; Della Chiesa, M.; Bertaina, A.; Pagliara, D.; Merli, P.; Indio, V.; Galaverna, F.; Algeri, M.; Moretta, F.; Colomar-Carando, N.; Muccio, L.; Sivori, S.; Pession, A.; Mingari, M.C.; Moretta, L.; Moretta, A.; Locatelli, F.; Pende, D. Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia. Cancers 2020, 12, 2187. https://doi.org/10.3390/cancers12082187
Meazza R, Falco M, Loiacono F, Canevali P, Della Chiesa M, Bertaina A, Pagliara D, Merli P, Indio V, Galaverna F, Algeri M, Moretta F, Colomar-Carando N, Muccio L, Sivori S, Pession A, Mingari MC, Moretta L, Moretta A, Locatelli F, Pende D. Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia. Cancers. 2020; 12(8):2187. https://doi.org/10.3390/cancers12082187
Chicago/Turabian StyleMeazza, Raffaella, Michela Falco, Fabrizio Loiacono, Paolo Canevali, Mariella Della Chiesa, Alice Bertaina, Daria Pagliara, Pietro Merli, Valentina Indio, Federica Galaverna, Mattia Algeri, Francesca Moretta, Natalia Colomar-Carando, Letizia Muccio, Simona Sivori, Andrea Pession, Maria Cristina Mingari, Lorenzo Moretta, Alessandro Moretta, Franco Locatelli, and Daniela Pende. 2020. "Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia" Cancers 12, no. 8: 2187. https://doi.org/10.3390/cancers12082187