Volume 19, Issue 6, Pages (June 2017)

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Volume 19, Issue 6, Pages (June 2017)

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Volume 19, Issue 6, Pages 710-720 (June 2017) Natural killer cells differentiated in vitro from cord blood CD34+ cells are more advantageous for use as an immunotherapy than peripheral blood and cord blood natural killer cells Anna Domogala, Michael Blundell, Adrian Thrasher, Mark W. Lowdell, J. Alejandro Madrigal, Aurore Saudemont Cytotherapy Volume 19, Issue 6, Pages 710-720 (June 2017) DOI: 10.1016/j.jcyt.2017.03.068 Copyright © 2017 International Society for Cellular Therapy Terms and Conditions

Figure 1 Proliferation of CBCD34+ NK, PBNK and CBNK cells after cytokine stimulation. Proliferation of CBCD34+ NK, PBNK and CBNK cells was assessed by CFSE analysis after stimulation with 200 IU of IL-2 for CBCD34+ and PBNK cells and 1000 IU of IL-2 for CBNK cells (A) or 20 ng/mL IL-15 (B). The median MFI of CFSE (±range) CBCD34+ NK (n = 4), PBNK (n = 4) and CBNK (n = 4) cells is shown. Statistical analysis was performed using Mann-Whitney test; only significant differences are shown. *P < 0.05. Cytotherapy 2017 19, 710-720DOI: (10.1016/j.jcyt.2017.03.068) Copyright © 2017 International Society for Cellular Therapy Terms and Conditions

Figure 2 Expression of differentiation markers by CBCD34+ NK, PBNK and CBNK cells. (A) Expression of EOMES and T-bet was analyzed by RT-PCR. The relative expression of messenger RNA was normalized to that of the mean of the two reference genes β2M and ATP5B. The median relative expression (±range) of CBCD34+ NK (n = 6), PBNK (n = 6) and CBNK (n = 6) cells is shown. (B) Telomere length analysis was carried out using a telomere PNA kit. Median relative telomere length (±range) of CBCD34+ NK cells (n = 6), PBNK cells (n = 6) and CBNK cells (n = 6) is shown. (C) Percentage CD57 expression (±range) of CBCD34+ NK (n = 9), PBNK (n = 9) and CBNK (n = 9) cells is shown. Statistical analysis was performed using Mann-Whitney test; only significant differences are shown.**P < 0.01; ***P < 0.001. Cytotherapy 2017 19, 710-720DOI: (10.1016/j.jcyt.2017.03.068) Copyright © 2017 International Society for Cellular Therapy Terms and Conditions

Figure 3 Killing of AML and K562 cells in vitro. In vitro killing was analyzed by a flow cytometry–based cytotoxicity assay. (A) Median specific K562 lysis (±range) by CBCD34+ NK (n = 8), PBNK (n = 8) and CBNK (n = 5) cells. (B) Median specific AML lysis (±range) by CBCD34+ NK (n = 18), PBNK (n = 18) and CBNK (n = 9) cells in vitro. Cytotherapy 2017 19, 710-720DOI: (10.1016/j.jcyt.2017.03.068) Copyright © 2017 International Society for Cellular Therapy Terms and Conditions

Figure 4 CTV-1 lysate primes resting NK cells to lyse AML and K562 cells in vitro. In vitro killing was analyzed by a flow cytometry–based cytotoxicity assay. (A) Median specific K562 lysis (±range) by resting CBCD34+ NK cells (n = 10) and primed CBCD34+ NK cells (n = 10). (B) Median specific AML lysis (±range) by resting CBCD34+ NK cells (n = 27) and primed CBCD34+ NK cells (n = 27). (C) Median specific lysis (±range) by primed CBCD34+ NK (n = 15), PBNK (n = 15) and CBNK (n = 15) cells. Statistical analysis was performed using Mann-Whitney test. *P < 0.05; ***P < 0.001. Cytotherapy 2017 19, 710-720DOI: (10.1016/j.jcyt.2017.03.068) Copyright © 2017 International Society for Cellular Therapy Terms and Conditions

Figure 5 Killing of patient AML blasts, K562 cells and RAJI cells by resting, primed and IL-2 stimulated CBCD34+ NK, PBNK and CBNK cells. In vitro killing was analyzed by a flow cytometry–based cytotoxicity assay. Median specific lysis (±range) of AML (n = 15), K562 cells (n = 5) and RAJI cells (n = 5) by CBCD34+ NK (A), PBNK (B) and CBNK (C) cells is shown. Statistical analysis was performed using Mann-Whitney test; only significant differences are shown. *P < 0.05; **P < 0.01; ***P < 0.001. Cytotherapy 2017 19, 710-720DOI: (10.1016/j.jcyt.2017.03.068) Copyright © 2017 International Society for Cellular Therapy Terms and Conditions

Figure 6 Killing of AML cells in vivo by resting and primed CBCD34+ NK cells. (A) Median percentage of PKH26-labeled AML cells (±range) detected in the bone marrow, liver, lungs and spleen (n = 6). (B) Median percentage of NK cells (±range) detected in the bone marrow, liver, lungs and spleen (n = 6). Statistical analysis was performed using Mann-Whitney test; only significant differences are shown. **P < 0.01. Cytotherapy 2017 19, 710-720DOI: (10.1016/j.jcyt.2017.03.068) Copyright © 2017 International Society for Cellular Therapy Terms and Conditions

Figure 7 Killing of solid tumor cell lines by resting, primed and IL-2 stimulated CBCD34+ NK, PBNK and CBNK cells. In vitro killing was analyzed by a flow cytometry–based cytotoxicity assay. (A) Median specific lysis (±range) of MCF-7 by resting, primed and IL-2 stimulated CBCD34+ (n = 6), PBNK (n = 6) and CBNK (n = 6) cells. (B) Median specific lysis (±range) of HT-29 by resting, primed and IL-2 stimulated CBCD34+ (n = 6), PBNK (n = 6) and CBNK (n = 6) cells. (C) Median specific lysis (±range) of 1520 by resting, primed and IL-2 stimulated CBCD34+ (n = 6), PBNK (n = 6) and CBNK (n = 6) cells. (D) Median specific lysis (±range) of A478 by resting, primed and IL-2 stimulated CBCD34+ (n = 6), PBNK (n = 6) and CBNK (n = 6) cells. Statistical analysis was performed using Mann-Whitney test; only significant differences are shown. *P < 0.05; **P < 0.01. Cytotherapy 2017 19, 710-720DOI: (10.1016/j.jcyt.2017.03.068) Copyright © 2017 International Society for Cellular Therapy Terms and Conditions

Figure 8 Blocking of TRAIL, FasL, NKG2D and CD16 on CBCD34+, PBNK and CBNK cells. Receptor involvement was analyzed by blocking before priming and before performing an in vitro killing assay against the NK-resistant cell line RAJI. (A) Median specific lysis (±range) by resting, primed isotype, primed and primed TRAIL-blocked CBCD34+ (n = 6), PBNK (n = 6) and CBNK (n = 6) cells. (B) Median specific lysis (±range) by resting, primed isotype, primed and primed FasL-blocked CBCD34+ (n = 6), PBNK (n = 6) and CBNK (n = 6) cells. (C) Median specific lysis (±range) by resting, primed isotype, primed and primed NKG2D-blocked CBCD34+ (n = 6), PBNK (n = 6) and CBNK (n = 6) cells. (D) Median specific lysis (±range) by resting, primed isotype, primed and primed CD16-blocked CBCD34+ (n = 6), PBNK (n = 6) and CBNK (n = 6) cells. Statistical analysis was performed using Mann-Whitney test; only significant differences are shown. *P < 0.05; **P < 0.01; ***P < 0.001. Cytotherapy 2017 19, 710-720DOI: (10.1016/j.jcyt.2017.03.068) Copyright © 2017 International Society for Cellular Therapy Terms and Conditions