Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma by Bethany Mundy-Bosse, Nathan Denlinger,

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Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma by Bethany Mundy-Bosse, Nathan Denlinger, Eric McLaughlin, Nitin Chakravarti, Susan Hwang, Li Chen, Hsiaoyin Charlene Mao, David Kline, Youssef Youssef, Rebecca Kohnken, Dean Anthony Lee, Gerard Lozanski, Aharon G. Freud, Pierluigi Porcu, Basem William, Michael A. Caligiuri, and Anjali Mishra BloodAdv Volume 2(15):1818-1827 August 14, 2018 © 2018 by The American Society of Hematology

Bethany Mundy-Bosse et al. Blood Adv 2018;2:1818-1827 © 2018 by The American Society of Hematology

NK-cell number and correlation with CTCL patient survival. NK-cell number and correlation with CTCL patient survival. (A) Absolute NK-cell numbers were calculated in normal donors (n = 51; mean ± standard error of the mean [SEM], 0.2442 ± 0.02 ) and CTCL patients (n = 121; 0.208 ± 0.01; P = .08). (B) Kaplan-Meier curves for overall survival at possible absolute NK-cell counts in CTCL patients (n = 121). (C) NK cells, CD56+/lineage (CD3/CD14/CD20), were isolated from freshly obtained peripheral blood samples from CTCL patients and normal control donors. (D) Purified NK cells were co-cultured with K562 leukemic targets in a standard chromium release assay at indicated ratios. Data are presented as mean ± SEM. *P ≤ .05; **P ≤ .01; ***P ≤ .001; unpaired 2-tailed Student t test. FSC, forward scatter; ns, not significant; SSC, side scatter. Bethany Mundy-Bosse et al. Blood Adv 2018;2:1818-1827 © 2018 by The American Society of Hematology

Differential RNA expression analysis in CTCL patients. Differential RNA expression analysis in CTCL patients. NK cells were isolated from CTCL patients and normal donors and evaluated by RNA sequencing. (A) Heat map of differentially regulated transcripts among normal donors (n = 3) and CTCL MF (n = 5) and CTCL SS (n = 2) patients. (B) Mediators of cytolytic activity and NK-cell activation were evaluated in all CTCL patients compared with normal controls. Perforin mean ± SEM of transcript in healthy donor vs CTCL patients for NK cells (91.39 ± 9.18 [n = 3] vs 485.7 ± 43.15 [n = 7]; P = .0004), granzyme A (GZMA) (58.15 ± 6.605 [n = 3] vs 218.7 ± 29.78 [n = 7]; P = .0094), granzyme B (GZMB) (143 ± 23.79 [n = 3] vs 431 ± 68.13 [n = 7]; P = .03), Fas (1.413 ± 0.01849 [n = 3] vs 3.967 ± 0.4395 [n = 7]; P = .0063), tumor necrosis factor-alpha–related apoptosis-inducing ligand (TRAIL) (3.756 ± 0.4925 [n = 3] vs 7.634 ± 1.033 [n = 7]; P = .0477), and IFN-G (2.861 ± 0.5007 [n = 3] vs 7.325 ± 1.621 [n = 7]; P = .1218). (C) An ingenuity pathway analysis upstream functional analysis was performed in an enriched data set from the NK cells. Red indicates upregulation in CTCL patients compared with normal donors; green indicates reduced expression. (D) RNA expression of receptor components required for both IL-2 and IL-15 signaling were evaluated in CTCL patients and compared with that in normal donors (IL-15Rα: mean ± SEM of relative RNA in normal vs CTCL, 0.8677 ± 0.1018 [n = 3] vs 1.772 ± 0.2055 [n = 7]; P = .03; IL-15Rγ, 57.02 ± 7.525 [n = 3] vs 154.7 ± 12.14 [n = 7]; P = .001. IL-15Rβ was also elevated (128 ± 23.68 [n = 3] vs 223.2 ± 25.43 [n = 7]; P = .056). (E) Protein expression of pSTAT3 and pSTAT5 on NK cells was determined in freshly obtained whole blood samples from CTCL patients and matched with that of normal donors by flow cytometry. Graph indicates mean fluorescence intensity (MFI) of normal (gray bars [n = 7]) compared with CTCL patients (green bars [n = 14]); pSTAT3: normal, 2417 ± 154.1 (n = 7) vs CTCL, 2734 ± 199; P = .32; pSTAT5: normal, 1253 ± 50.23 (n = 8) vs CTCL, 1405 ± 64.35; P = .028. (F) Schematic of interaction between malignant CD4+ T cells in CTCL patients producing IL-15, which binds to the upregulated IL-15 receptor complex on NK cells and enhances downstream activating pathways in NK cells. Data are presented as mean ± SEM. *P ≤ .05; **P ≤ .01; ***P ≤ .001; unpaired 2-tailed Student t test. FPKM, fragments per kilobase million. Bethany Mundy-Bosse et al. Blood Adv 2018;2:1818-1827 © 2018 by The American Society of Hematology