Laboratory of Animal Tumor Models, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
Cancer Immunol Res. 2019 Nov;7(11):1813-1823. doi: 10.1158/2326-6066.CIR-19-0026. Epub 2019 Sep 4.
Despite the great success of chimeric antigen receptor T (CAR-T)-cell therapy in the treatment of hematologic malignancies, CAR-T-cell therapy is limited in solid tumors, including hepatocellular carcinoma (HCC). NK group 2 member D (NKG2D) ligands (NKG2DL) are generally absent on the surface of normal cells but are overexpressed on malignant cells, offering good targets for CAR-T therapy. Indeed, analysis of The Cancer Genome Atlas and HCC tumor samples showed that the expression of most NKG2DLs was elevated in tumors compared with normal tissues. Thus, we designed a novel NKG2D-based CAR comprising the extracellular domain of human NKG2D, 4-1BB, and CD3ζ signaling domains (BBz). NKG2D-BBz CAR-T cells efficiently killed the HCC cell lines SMMC-7721 and MHCC97H , which express high levels of NKG2DLs, whereas they less efficiently killed NKG2DL-silenced SMMC-7721 cells or NKG2DL-negative Hep3B cells. Overexpression of MICA or ULBP2 in Hep3B improved the killing capacity of NKG2D-BBz CAR-T cells. T cells expressing the NKG2D-BBz CAR effectively eradicated SMMC-7721 HCC xenografts. Collectively, these results suggested that NKG2D-BBz CAR-T cells could potently eliminate NKG2DL-high HCC cells both and , thereby providing a promising therapeutic intervention for patients with NKG2DL-positive HCC.
尽管嵌合抗原受体 T（CAR-T）细胞疗法在治疗血液恶性肿瘤方面取得了巨大成功，但 CAR-T 细胞疗法在实体瘤中受到限制，包括肝细胞癌（HCC）。NK 组 2 成员 D（NKG2D）配体（NKG2DL）通常不在正常细胞表面表达，但在恶性细胞中过度表达，为 CAR-T 治疗提供了良好的靶点。事实上，对 The Cancer Genome Atlas 和 HCC 肿瘤样本的分析表明，与正常组织相比，大多数 NKG2DL 的表达在肿瘤中升高。因此，我们设计了一种新型基于 NKG2D 的 CAR，包含人 NKG2D 的细胞外结构域、4-1BB 和 CD3ζ 信号结构域（BBz）。NKG2D-BBz CAR-T 细胞有效地杀死了表达高水平 NKG2DL 的 HCC 细胞系 SMMC-7721 和 MHCC97H，而对 NKG2DL 沉默的 SMMC-7721 细胞或 NKG2DL 阴性的 Hep3B 细胞的杀伤效率较低。在 Hep3B 中过表达 MICA 或 ULBP2 可提高 NKG2D-BBz CAR-T 细胞的杀伤能力。表达 NKG2D-BBz CAR 的 T 细胞有效根除了 SMMC-7721 HCC 异种移植物。总之，这些结果表明，NKG2D-BBz CAR-T 细胞可以有效消除 NKG2DL 高 HCC 细胞，从而为 NKG2DL 阳性 HCC 患者提供了一种有前途的治疗干预措施。
