Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells.

Abstract

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 in vitro, 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 in vitro and in vivo, thereby providing a promising therapeutic intervention for patients with NKG2DL-positive HCC.

• Authors: Bin Sun, Dong Yang, Hongjiu Dai, Xiuyun Liu, Ru Jia, Xiaoyue Cui, Wenxuan Li, Changchun Cai, Jianming Xu, Xudong Zhao
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 7 Issue 11 Pg. 1813-1823 (Nov 2019) ISSN: 2326-6074 [Electronic] United States
• PMID: 31484657 (Publication Type: Journal Article)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• KLRK1 protein, human
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, Chimeric Antigen

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, metabolism, therapy)
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• Gene Expression Regulation, Neoplastic
• Humans
• Immunotherapy, Adoptive
• Liver Neoplasms (genetics, metabolism, therapy)
• Mice
• Mice, Inbred NOD
• Mice, Transgenic
• NK Cell Lectin-Like Receptor Subfamily K (genetics, metabolism)
• Receptors, Chimeric Antigen (genetics, metabolism)
• Signal Transduction
• T-Lymphocytes (immunology, metabolism, transplantation)
• Xenograft Model Antitumor Assays