Johnson Jenna K, Miller Jeffrey S
Department of Medicine, Division of Hematology, Oncology, and Transplantation, Masonic Cancer Center, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
Medical Scientist Training Program, University of Minnesota, Minneapolis, Minnesota.
Int J Immunogenet. 2018 Jul 16. doi: 10.1111/iji.12387.
Natural killer (NK) cells recognize targets that have been changed via malignant transformation or infection. Previously, NK cells were thought to be short-lived, but we now know that NK cells can be long-lived and remember past exposures in response to CMV. NK cells use a plethora of activating and inhibitory receptors to recognize these changes and attack targets, but tumour cells often evade NK cells. Therefore, major efforts are being made to hone in on NK cell antitumour properties in immunotherapy. In the clinical setting, haploidentical NK cells can be adoptively transferred to help treat cancer. To expand NK cells in vivo and enhance tumour targeting, IL-15 is being tested in combination with a glycogen synthase kinase (GSK) 3 inhibitor (CHIR99021), an inhibitor that has been shown to expand mature, highly functional NK cells capable of killing multiple tumour targets. One major limitation to NK cell therapy is lack of specificity. To address this concern, bispecific or trispecific engagers that target NK cells to the tumour and an ADAM17 inhibitor that prevents CD16 shedding after NK cell activation are being tested. Additionally, monoclonal antibodies are being designed to redirect the inhibitory signals that limit NK cell functionality. Further understanding of the biology of NK cells will inform strategies to exploit NK cells for therapeutic purposes.
自然杀伤（NK）细胞能够识别因恶性转化或感染而发生改变的靶标。以前，人们认为NK细胞寿命较短，但现在我们知道NK细胞可以长期存活，并能记住过去对巨细胞病毒（CMV）暴露的反应。NK细胞利用大量激活受体和抑制受体来识别这些变化并攻击靶标，但肿瘤细胞常常逃避NK细胞的攻击。因此，免疫治疗领域正在大力致力于挖掘NK细胞的抗肿瘤特性。在临床环境中，单倍体相合的NK细胞可以通过过继性转移来辅助治疗癌症。为了在体内扩增NK细胞并增强肿瘤靶向性，白细胞介素-15（IL-15）正在与糖原合酶激酶（GSK）3抑制剂（CHIR99021）联合进行试验，该抑制剂已被证明能够扩增成熟的、具有高功能的NK细胞，这些细胞能够杀伤多种肿瘤靶标。NK细胞疗法的一个主要局限性是缺乏特异性。为了解决这一问题，正在试验将NK细胞靶向肿瘤的双特异性或三特异性衔接分子以及一种在NK细胞激活后阻止CD16脱落的ADAM17抑制剂。此外，正在设计单克隆抗体来重新引导限制NK细胞功能的抑制信号。对NK细胞生物学的进一步了解将为利用NK细胞进行治疗的策略提供依据。
