Wang Zhongjuan, Guo Linghua, Song Yuan, Zhang Yinsheng, Lin Dandan, Hu Bo, Mei Yu, Sandikin Dedy, Liu Haiyan
Institute of Blood and Marrow Transplantation, Department of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, 28 Medical Dr., Singapore, 117456, Singapore.
Cancer Immunol Immunother. 2017 Apr;66(4):537-548. doi: 10.1007/s00262-017-1959-1. Epub 2017 Feb 9.
The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor). NK-92 cells expressing TN receptors were resistant to TGF-β-induced suppressive signaling and did not down-regulate NKG2D. These modified NK-92 cells had higher killing capacity and interferon γ (IFN-γ) production against tumor cells compared with the control cells and their cytotoxicity could be further enhanced by TGF-β. More interestingly, the NK-92 cells expressing TN receptors were better chemo-attracted to the tumor cells expressing TGF-β. The presence of these modified NK-92 cells significantly inhibited the differentiation of human naïve CD4 T cells to regulatory T cells. NK-92-TN cells could also inhibit tumor growth in vivo in a hepatocellular carcinoma xenograft tumor model. Therefore, TN chimeric receptors can be a novel strategy to augment anti-tumor efficacy in NK cell adoptive therapy.
自然杀伤（NK）细胞无需特异性抗原识别就能杀伤肿瘤细胞的能力使其相对于T细胞具有优势，使其成为肿瘤免疫治疗的潜在效应细胞。然而，NK细胞过继性疗法的疗效可能会受到免疫抑制性肿瘤微环境的限制。转化生长因子-β（TGF-β）是一种强效的免疫抑制细胞因子，可抑制NK细胞功能。为了将TGF-β诱导的抑制信号转化为激活信号，我们对NK-92细胞进行基因改造，使其表达一种嵌合受体，该受体具有TGF-β II型受体的细胞外和跨膜结构域以及NK细胞激活受体NKG2D的细胞内结构域（TN嵌合受体）。表达TN受体的NK-92细胞对TGF-β诱导的抑制信号具有抗性，并且不会下调NKG2D。与对照细胞相比，这些经过改造的NK-92细胞对肿瘤细胞具有更高的杀伤能力和干扰素γ（IFN-γ）产生量，并且它们的细胞毒性可被TGF-β进一步增强。更有趣的是，表达TN受体的NK-92细胞对表达TGF-β的肿瘤细胞具有更好的趋化作用。这些经过改造的NK-92细胞的存在显著抑制了人类初始CD4 T细胞向调节性T细胞的分化。NK-92-TN细胞在肝细胞癌异种移植肿瘤模型中也能在体内抑制肿瘤生长。因此，TN嵌合受体可以成为增强NK细胞过继性疗法抗肿瘤疗效的一种新策略。
