Bergerson Rachel J, Williams Robin, Wang Hongbo, Shanley Ryan, Colbenson Gretchen, Kerber Alyssa, Cooley Sarah, Curtsinger Julie, Felices Martin, Miller Jeffrey S, Verneris Michael R
Department of Pediatrics, Masonic Cancer Center, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN.
Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
Blood Adv. 2016 Dec 27;1(3):208-218. doi: 10.1182/bloodadvances.2016000158. Epub 2016 Oct 30.
Natural Killer (NK) cell immune reconstitution after double umbilical cord blood transplantation (dUCBT) is rapid and thought to be involved in graft vs. leukemia (GvL) reactions. To investigate the role of NK cell recovery on clinical outcomes, the absolute number of NK cells at Day 28 after dUCBT was determined and patients with low numbers of NK cells had inferior two year disease-free survival (hazard ratio 1.96; p=0.04). A detailed developmental and functional analysis of the recovering NK cells was performed to link NK recovery and patient survival. The proportion of NK cells in each developmental stage was similar for patients with low, medium, and high Day 28 NK cell numbers. As compared to healthy controls, patients post-transplant showed reduced NK functional responses upon K562 challenge (CD107a, IFN-γ, and TNFα); however, there were no differences based on Day 28 NK cell number. Patients with low NK numbers had 30% less STAT5 phosphorylation in response to exogenous IL-15 (p=0.04) and decreased Eomes expression (p=0.025) compared to patients with high NK numbers. Decreased STAT5 phosphorylation and Eomes expression may be indicative of reduced sensitivity to IL-15 in the low NK cell group. Incubation of patient samples with IL-15 superagonist (ALT803) increased cytotoxicity and cytokine production in all patient groups. Thus, clinical interventions, including administration of IL-15 early after transplantation may increase NK cell number and function and, in turn, improve transplantation outcomes.
双份脐带血移植（dUCBT）后自然杀伤（NK）细胞免疫重建迅速，且被认为参与了移植物抗白血病（GvL）反应。为了研究NK细胞恢复对临床结局的作用，测定了dUCBT后第28天NK细胞的绝对数量，NK细胞数量低的患者两年无病生存率较差（风险比1.96；p=0.04）。对恢复中的NK细胞进行了详细的发育和功能分析，以将NK细胞恢复与患者生存联系起来。第28天NK细胞数量低、中、高的患者在每个发育阶段的NK细胞比例相似。与健康对照相比，移植后患者在K562刺激下的NK功能反应降低（CD107a、IFN-γ和TNFα）；然而，根据第28天的NK细胞数量没有差异。与NK细胞数量高的患者相比，NK细胞数量低的患者对外源性IL-15的反应中STAT5磷酸化减少30%（p=0.04），Eomes表达降低（p=0.025）。STAT5磷酸化和Eomes表达降低可能表明低NK细胞组对IL-15的敏感性降低。用IL-15超激动剂（ALT803）孵育患者样本可增加所有患者组的细胞毒性和细胞因子产生。因此，包括移植后早期给予IL-15在内的临床干预可能会增加NK细胞数量和功能，进而改善移植结局。
