Veluchamy John P, Heeren A Marijne, Spanholtz Jan, van Eendenburg Jaap D H, Heideman Daniëlle A M, Kenter Gemma G, Verheul Henk M, van der Vliet Hans J, Jordanova Ekaterina S, de Gruijl Tanja D
Department of Medical Oncology, VU (Vrije Universiteit) University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
Glycostem Therapeutics, Oss, The Netherlands.
Cancer Immunol Immunother. 2017 Jan;66(1):51-61. doi: 10.1007/s00262-016-1919-1. Epub 2016 Oct 25.
Down-regulation of HLA in tumor cells, low numbers and dysfunctionality of NK cells are commonly observed in patients with end-stage cervical cancer. Adoptive transfer of high numbers of cytotoxic NK cells might be a promising treatment approach in this setting. Here, we explored the cytotoxic efficacy on ten cervical cancer cell lines of activated allogeneic NK cells from two sources, i.e., peripheral blood (PBNK) with and without cetuximab (CET), a tumor-specific monoclonal antibody directed against EGFR, or derived from umbilical cord blood (UCB-NK). Whereas CET monotherapy was ineffective against the panel of cervical cancer cell lines, irrespective of their EGFR expression levels and despite their RAS status, it significantly enhanced the in vitro cytotoxic efficacy of activated PBNK (P = 0.002). Equally superior cytotoxicity over activated PBNK alone was achieved by UCB-NK (P < 0.001). Both PBNK- and UCB-NK-mediated cytotoxic activity was dependent on the NK-activating receptors natural killer group 2, member D receptor (NKG2D) and DNAX accessory molecule-1 (DNAM-1) (P < 0.05) and unrelated to expression levels of the inhibitory receptors HLA-E and/or HLA-G. Most strikingly, whereas the PBNK's cytotoxic activity was inversely correlated with HLA-ABC levels (P = 0.036), PBNK + CET and UCB-NK cytotoxicity were entirely independent of HLA-ABC expression. In conclusion, this study provides a rationale to initiate a clinical trial for cervical cancer with adoptively transferred allogeneic NK cells, employing either UCB-NK or PBNK + CET for EGFR-expressing tumors. Adoptive transfer of UCB-NK might serve as a generally applicable treatment for cervical cancer, enabled by HLA-, histology- and HPV-independent killing mechanisms.
在晚期宫颈癌患者中,通常可观察到肿瘤细胞中HLA下调、自然杀伤细胞(NK细胞)数量减少及功能失调。在这种情况下,大量输注具有细胞毒性的NK细胞可能是一种有前景的治疗方法。在此,我们探究了来自两种来源的活化异体NK细胞对十种宫颈癌细胞系的细胞毒性作用,这两种来源分别是外周血(PBNK),其使用或不使用西妥昔单抗(CET),西妥昔单抗是一种针对表皮生长因子受体(EGFR)的肿瘤特异性单克隆抗体,以及来自脐带血的NK细胞(UCB-NK)。尽管CET单药治疗对该组宫颈癌细胞系无效,无论其EGFR表达水平如何,也不管其RAS状态如何,但它显著增强了活化PBNK的体外细胞毒性作用(P = 0.002)。UCB-NK同样实现了比单独活化PBNK更优异的细胞毒性(P < 0.001)。PBNK和UCB-NK介导的细胞毒性活性均依赖于NK激活受体自然杀伤细胞2族D成员受体(NKG2D)和DNAX辅助分子-1(DNAM-1)(P < 0.05),且与抑制性受体HLA-E和/或HLA-G的表达水平无关。最引人注目的是,尽管PBNK的细胞毒性活性与HLA-ABC水平呈负相关(P = 0.036),但PBNK + CET和UCB-NK的细胞毒性与HLA-ABC表达完全无关。总之,本研究为开展一项宫颈癌临床试验提供了理论依据,该试验采用异体NK细胞过继性转移,对于表达EGFR的肿瘤使用UCB-NK或PBNK + CET。UCB-NK的过继性转移可能作为一种普遍适用的宫颈癌治疗方法,这得益于其不依赖HLA、组织学和人乳头瘤病毒(HPV)的杀伤机制。