Eradication of Hepatocellular Carcinoma by NKG2D-specific CAR T-cells

author:	Sun B, Yang D, Dai H, Liu X, Jia R, Cui X, Li W, Cai C, Xu J, Zhao X
Abstract:	Despite the great success of chimeric antigen receptor T (CAR-T) cell therapy in the treatment of hematological malignancies, CAR-T cell therapy is limited in solid tumors, including hepatocellular carcinoma (HCC). NKG2D ligands (NKG2DLs) 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-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 NKG2DL-positive HCC patients
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PubYear:	2019
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Unit code:	152453
Publication name:	Cancer Immunology Research
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Paper source:	https://cancerimmunolres.aacrjournals.org/content/early/2019/09/04/2326-6066.CIR-19-0026.long
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