Reconstitution of Natural Killer Cells in HLA-Matched HSCT after Reduced-Intensity Conditioning: Impact on Clinical Outcome Caroline Pical-Izard, Roberto.

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Reconstitution of Natural Killer Cells in HLA-Matched HSCT after Reduced-Intensity Conditioning: Impact on Clinical Outcome Caroline Pical-Izard, Roberto Crocchiolo, Samuel Granjeaud, Eloise Kochbati, Sylvaine Just-Landi, Christian Chabannon, Coralie Frassati, Christophe Picard, Didier Blaise, Daniel Olive, Cyril Fauriat Biology of Blood and Marrow Transplantation Volume 21, Issue 3, Pages 429-439 (March 2015) DOI: 10.1016/j.bbmt.2014.11.681 Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Rapid reconstitution of NK cells after HLA-matched HSCT. Kinetics of NK cell reconstitution after MRD (plain line) or MUD (dashed line) HSCT. NK cell counts (mean ± SEM) were measured at the indicated time points postgraft and compared with each other and with healthy controls (mean ± SEM, gray shade). NK cell numbers for MUD patients at 4 to 6 months could not be determined. *P < .05 (comparison between MRD, MUD patients values versus healthy control subjects). Biology of Blood and Marrow Transplantation 2015 21, 429-439DOI: (10.1016/j.bbmt.2014.11.681) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Reconstituting NK cells display an immature phenotype. (A) PBMCs were stained with anti-CD3, CD56, and CD16 mAbs. Samples were analyzed by flow cytometry, and representative fluorescent activated cell sorter plots are shown for 1 patient at different times after graft (indicated within each plots). The proportions of CD56bright CD16neg/low, and CD56 dim CD16high indicated in the gates were calculated in the CD3– live cell lymphocyte population. m indicates months; DCM, dead cell marker. (B) The frequencies of CD56bright (left) and CD56dim NK cells (right) among total NK cells are represented in healthy control subjects (HC, black boxes) and in patients transplanted with a HLA-MRD (white boxes) and a, HLA-MUD (gray boxes) at different time points after graft. (C) Expression of NKG2A (left) and CD57 (right) were analyzed on CD56dim NK cells in healthy control subjects (HC, black boxes) and in patients transplanted with a HLA-MRD (white boxes) and a HLA- MUD (gray boxes) at different time points after graft. Data represent Tukey whisker boxes, with outliers represented as round dots. When indicated, a Kruskal-Wallis nonparametric test with Dunns post-test was performed to compute the P value for the comparisons. *P < .05, **P < .01, ***P < .001. Biology of Blood and Marrow Transplantation 2015 21, 429-439DOI: (10.1016/j.bbmt.2014.11.681) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Expression of the main KIR by developing NK cells. Expression of KIR2DL1/S1 (left), KIR2DL2/L3/S2 (middle), and KIR3DL1 (right) were analyzed on CD56dim NK cells in healthy control subjects (HC, black boxes) and in patients transplanted with an HLA-MRD (white boxes) and an HLA-MUD (gray boxes) at different time points after graft. Data represent Tukey whisker boxes, with outliers represented as round dots. When indicated, a Kruskal-Wallis nonparametric test with Dunns post-test was performed to compute the P value for the comparisons. *P < .05, **P < .01, ***P < .001. Biology of Blood and Marrow Transplantation 2015 21, 429-439DOI: (10.1016/j.bbmt.2014.11.681) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Dissociation between NK cells degranulation and cytokine production. (A) NK cells from healthy control subjects (HC) and patients at different time points were co-cultured with K562 cells for 4 hours and stained for surface CD107a, or intracellular MIP-1β, IFN-γ, or TNF-α. Data represent the relative proportion (frequency) of the indicated responses measured. (B) Comparison of CD107a, MIP-1β, IFN-γ, and TNF-α production after interaction with K562 cells between patients grafted with cells from MRDs or MUDs. Data represent Tukey whisker boxes, with outliers represented as round dots. When indicated, a Kruskal-Wallis nonparametric test with Dunns post-test was performed to compute the P value for the comparisons. *P < .05, **P < .01, ***P < .001. Biology of Blood and Marrow Transplantation 2015 21, 429-439DOI: (10.1016/j.bbmt.2014.11.681) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Normal cytokine production by reconstituting NK cells upon exogenous cytokine stimulation. (A) Production of TNF-α and IFN-γ by NK cells from healthy control subjects (HC, n = 3) and patients 1 month after HSCT (n = 3) in response to IL-12/IL-18 stimulation. (B) PBMCs from healthy control subjects (HC, black bars) and recipients 1 month after HSCT (gray bars) were incubated overnight with media alone or with IL-12/IL-18 and then co-cultured with K562 cells or with medium alone for 4 hours. After incubation, CD107a expression and TNF-α and IFN-γ production were measured on CD56+CD3– NK cells. Bars represent the mean ± SEM. (C) NK cells were stimulated with IL-12+IL-18 and co-cultured with K562 for 4 hours. CD56dim NK cells were gated and a Boolean gating strategy was used for analysis. We analyzed the proportion of the different types of responses displayed by responding NK cells. Pie charts represent the frequency of cells positive for the given number of measured responses (CD107a, TNF-α, and IFN-γ). Cells are plotted against the number of responses they display. Arcs depict the relative frequency of cells specifically positive for CD107a, TNF-α, and IFN-γ staining, as indicated. Values represent the mean of 3 different patients. Biology of Blood and Marrow Transplantation 2015 21, 429-439DOI: (10.1016/j.bbmt.2014.11.681) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 Expansion of NKG2A–NKG2C+CD57+ CD56dim NK cells after HSCT. (A) NKG2A negative CD56dim NK cells from healthy control subjects (HC, white bars) and patients at different time points after HSCT were gated into CD57+NKG2C+, CD57+NKG2C–, CD57–NKG2C+, or CD57–NKG2C–populations. (B) The total CD56dim NK cells (white bars) and the NKG2A–CD57+NKG2C+ population (black bars) were classified according to the number and the type of KIRs markers expressed on their surface. (C) Frequencies of NKG2A–CD57+NKG2C+ CD56dim NK cells are depicted according to the CMV activation status of the patients (left) or donors (right). (D) Frequencies of NKG2A–CD57+NKG2C+ CD56dim NK cells in the presence or absence of CMV reactivation after HSCT. Bars represent the means ± SEM. When indicated, a Kruskal-Wallis nonparametric test with Dunns post-test was performed to compute the P value for the comparisons between the different subsets with the corresponding subset in HC. *P < .05, **P < .01, ***P < .001. Biology of Blood and Marrow Transplantation 2015 21, 429-439DOI: (10.1016/j.bbmt.2014.11.681) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 NK cell reconstitution correlates with clinical outcome. (A) OS according to percentage of NK cells producing TNF-α at 1 month after HSCT. Survival of patients with <3.5% of TNF-α–producing cells (n = 6) was 0%, versus 75% of those with >3.5% (n = 7); P < .0001. (B) Relapse incidence according to percentage of NK cells producing TNF-α at 1 month after HSCT. Relapse of patients with <3.5% of TNF-α–producing cells (n = 6) was 83%, versus 31% of those with >3.5% (n = 7); P = .01. (C) Relapse incidence according to degranulation measured as the percentage of CD107a+ NK cells. Relapse of patients with <10% of CD107a+ cells (n = 4) was 75%, versus 22% of those with >10% (n = 10); P = .09. (D) OS according to percentage of CD56dim NK cells. Survival of patients with <30% of CD56dim cells (n = 7) was 43%, versus 81% of those with >30% (n = 16); P = .09). Patients at risk are indicated below each graph (left panels). Right panels correspond to the statistical relationships, displayed as Tukey whisker boxes, between the biological parameters obtained at 1 month postgraft and clinical outcome at 1 year with the focus of patient survival (alive at 12 months post-HSCT) or relapse (at 12 months). Patient numbers are indicated under the graphs. Biology of Blood and Marrow Transplantation 2015 21, 429-439DOI: (10.1016/j.bbmt.2014.11.681) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions