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Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells
Bin Sun1,2,3, Dong Yang1,2,3, Hongjiu Dai4
1Laboratory of Animal Tumor Models, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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.
Insights
Chimeric antigen receptor T (CAR-T)-cell therapy shows promise for hepatocellular carcinoma (HCC). NKG2D-based CAR-T cells effectively target and eliminate NKG2DL-high HCC cells in vitro and in vivo.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor T (CAR-T)-cell therapy is successful in hematologic cancers but limited in solid tumors like hepatocellular carcinoma (HCC).
- NK group 2 member D (NKG2D) ligands (NKG2DL) are overexpressed on malignant cells, making them potential targets for CAR-T therapy.
- NKG2DL expression is elevated in HCC tumors compared to normal tissues.
Purpose of the Study:
- To design and evaluate a novel NKG2D-based CAR-T cell therapy for hepatocellular carcinoma.
- To assess the efficacy of NKG2D-BBz CAR-T cells against HCC cells expressing NKG2DLs.
Main Methods:
- Designed a novel NKG2D-based CAR (NKG2D-BBz) incorporating human NKG2D, 4-1BB, and CD3ζ signaling domains.
- Tested NKG2D-BBz CAR-T cell cytotoxicity against HCC cell lines with varying NKG2DL expression levels in vitro.
- Evaluated the therapeutic effect of NKG2D-BBz CAR-T cells in an HCC xenograft mouse model in vivo.
Main Results:
- NKG2D-BBz CAR-T cells efficiently killed HCC cell lines (SMMC-7721, MHCC97H) with high NKG2DL expression.
- Killing capacity was reduced against NKG2DL-silenced or NKG2DL-negative HCC cells.
- Overexpressing MICA or ULBP2 enhanced CAR-T cell killing of Hep3B cells.
- NKG2D-BBz CAR-T cells eradicated SMMC-7721 HCC xenografts in vivo.
Conclusions:
- NKG2D-BBz CAR-T cells demonstrate potent efficacy against NKG2DL-high HCC cells both in vitro and in vivo.
- This approach offers a promising therapeutic strategy for patients with NKG2DL-positive HCC.
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