Department of Surgery, National University of Singapore, Singapore, Singapore.
Int J Cancer. 2014 Sep 15;135(6):1390-8. doi: 10.1002/ijc.28780. Epub 2014 Feb 28.
To develop more effective therapies for patients with advanced gastric cancer, we examined the potential of ex vivo expanded natural killer (NK) cells. We assessed the expression of ligands for NK Group 2 Member D (NKG2D, an important NK activation molecule) in primary tumors from 102 patients with gastric cancer by immunohistochemistry and determined their prognostic value. We then examined the in vitro and in vivo cytotoxicity of NK cells from healthy donors and patients with gastric cancer. The cytotoxicity of resting and of interleukin (IL)-2-activated NK cells was compared to that of NK cells expanded for 7 days by coculture with the K562-mb15-4.1BBL cell line. As a result, the expression of NKG2D ligands in primary tumors was correlated with favorable presenting features and outcomes, suggesting that gastric cancer may be sensitive to NK cell cytotoxicity. Although resting NK cells showed minimal cytotoxicity against gastric cancer cells, K562-mb15-4.1BBL-expanded NK cells were highly cytotoxic and significantly more powerful than IL-2-activated NK cells. Cytotoxicity was correlated with NKG2D ligand expression and could be modulated by mitogen-activated protein kinase and AKT-PI3 kinase inhibitors. The cytotoxicity of expanded NK cells against HER2-positive gastric cancer cells could be increased by Herceptin and further augmented by Lapatinib. Finally, expanded NK cells exhibited strong antitumor activity in immunodeficient mice engrafted with a gastric cancer cell line. In conclusion, gastric cancer tumors express NKG2D ligands and are highly susceptible to killing by NK cells stimulated by K562-mb15-4.1BBL. These results provide a strong rationale for clinical testing of these NK cells in patients and suggest their use to augment the effects of antibody therapy.
为了开发更有效的治疗方法来治疗晚期胃癌患者，我们研究了体外扩增自然杀伤 (NK) 细胞的潜力。我们通过免疫组织化学分析评估了 102 名胃癌患者的原发肿瘤中 NK 细胞组 2 成员 D (NKG2D，一种重要的 NK 激活分子)配体的表达，并确定了它们的预后价值。然后，我们检测了来自健康供体和胃癌患者的 NK 细胞的体外和体内细胞毒性。比较了静息和白细胞介素 (IL)-2 激活的 NK 细胞与通过与 K562-mb15-4.1BBL 细胞系共培养扩增 7 天的 NK 细胞的细胞毒性。结果，原发肿瘤中 NKG2D 配体的表达与有利的表现特征和结局相关，表明胃癌可能对 NK 细胞的细胞毒性敏感。尽管静息 NK 细胞对胃癌细胞的细胞毒性最小，但 K562-mb15-4.1BBL 扩增的 NK 细胞具有高度的细胞毒性，比 IL-2 激活的 NK 细胞强大得多。细胞毒性与 NKG2D 配体表达相关，并可通过丝裂原激活的蛋白激酶和 AKT-PI3 激酶抑制剂进行调节。用赫赛汀可增加扩增的 NK 细胞对 HER2 阳性胃癌细胞的细胞毒性，并进一步增强拉帕替尼的作用。最后，扩增的 NK 细胞在植入胃癌细胞系的免疫缺陷小鼠中表现出强烈的抗肿瘤活性。总之，胃癌肿瘤表达 NKG2D 配体，对 K562-mb15-4.1BBL 刺激的 NK 细胞杀伤高度敏感。这些结果为在患者中临床测试这些 NK 细胞提供了强有力的理由，并表明它们可用于增强抗体治疗的效果。
