Knorr David A, Bachanova Veronika, Verneris Michael R, Miller Jeffrey S
Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States.
Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, United States.
Semin Immunol. 2014 Apr;26(2):161-72. doi: 10.1016/j.smim.2014.02.002. Epub 2014 Mar 5.
Natural killer (NK) cells recognize deranged cells that display stress receptors or loss of major histocompatibility complex (MHC) class I. During development, NK cells become "licensed" only after they encounter cognate human leukocyte antigen (HLA) class I, leading to the acquisition of effector function. NK cells can be exploited for cancer therapy in several ways. These include targeting with monoclonal antibodies alone or combined with ex vivo and in vivo NK cell activation to facilitate adoptive immunotherapy using donor-derived NK cell products to induce graft-vs-tumor effects. In the adoptive transfer setting, persistence and in vivo expansion requires lymphodepleting chemotherapy to prevent rejection and provide homeostatic cytokines (such as IL-15) that activate NK cells. IL-15 has the advantage of avoiding regulatory T-cell expansion. Clinical applications are currently being tested. To enhance in vivo expansion, IL-2 has been used at low doses. However, low dose administration also leads to the stimulation of regulatory T cells. Monoclonal antibodies and bispecific killer engagers (BiKEs) may enhance specificity by targeting CD16 on NK cells to tumor antigens. Inhibition of CD16 shedding may also promote enhanced cytotoxicity. Future strategies include exploiting favorable donor immunogenetics or ex vivo expansion of NK cells from blood, progenitors, or pluripotent cells. Comparative clinical trials are needed to test these approaches.
自然杀伤（NK）细胞识别显示应激受体或主要组织相容性复合体（MHC）I类缺失的紊乱细胞。在发育过程中，NK细胞只有在遇到同源人类白细胞抗原（HLA）I类后才会“获得许可”，从而获得效应器功能。NK细胞可通过多种方式用于癌症治疗。这些方式包括单独使用单克隆抗体靶向，或与体外和体内NK细胞激活相结合，以促进使用供体来源的NK细胞产品进行过继性免疫治疗，从而诱导移植物抗肿瘤效应。在过继性转移环境中，NK细胞的持久性和体内扩增需要进行淋巴细胞清除化疗，以防止排斥反应，并提供激活NK细胞的稳态细胞因子（如IL-15）。IL-15具有避免调节性T细胞扩增的优势。目前正在对其临床应用进行测试。为了增强体内扩增，已使用低剂量的IL-2。然而，低剂量给药也会导致调节性T细胞的刺激。单克隆抗体和双特异性杀伤衔接器（BiKEs）可通过将NK细胞上的CD16靶向肿瘤抗原来提高特异性。抑制CD16的脱落也可能促进细胞毒性增强。未来的策略包括利用有利的供体免疫遗传学，或从血液、祖细胞或多能细胞中体外扩增NK细胞。需要进行比较临床试验来测试这些方法。
