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. 2021 Dec 16;36(1):10-21.
doi: 10.7555/JBR.35.20200207.

c-Met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells in vitro and in vivo

Xiaochen Huang  1   2   3 , Jiaojiao Guo  1   2 , Tao Li  1 , Lizhou Jia  1   2 , Xiaojun Tang  1 , Jin Zhu  4 , Qi Tang  1   2 , Zhenqing Feng  1   2   5
Affiliations

c-Met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells in vitro and in vivo

Xiaochen Huang et al. J Biomed Res. .

Abstract

c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma (HCC). Therefore, c-Met may serve as a promising target for HCC immunotherapy. Modifying T cells to express c-Met-specific chimeric antigen receptor (CAR) is an attractive strategy in treating c-Met-positive HCC. This study aimed to systematically evaluate the inhibitory effects of 2 nd- and 3 rd-generation c-Met CAR-T cells on hepatocellular carcinoma (HCC) cells. Here, 2 nd- and 3 rd-generation c-Met CARs containing an anti-c-Met single-chain variable fragment (scFv) as well as the CD28 signaling domain and CD3ζ (c-Met-28-3ζ), the CD137 signaling domain and CD3ζ (c-Met-137-3ζ), or the CD28 and CD137 signaling domains and CD3ζ (c-Met-28-137-3ζ) were constructed, and their abilities to target c-Met-positive HCC cells were evaluated in vitro and in vivo. All c-Met CARs were stably expressed on T cell membrane, and c-Met CAR-T cells aggregated around c-Met-positive HCC cells and specifically killed them in vitro. c-Met-28-137-3ζ CAR-T cells secreted more interferon-gamma (IFN-γ) and interleukin 2 (IL-2) than c-Met-28-3ζ CAR-T cells and c-Met-137-3ζ CAR-T cells. Compared with c-Met low-expressed cells, c-Met CAR-T cells secreted more cytokines when co-cultured with c-Met high-expressed cells. Moreover, c-Met-28-137-3ζ CAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups. This study suggests that 3 rd-generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2 nd-generation c-Met CAR-T cells, thereby providing a promising therapeutic intervention for c-Met-positive HCC.

Keywords: c-Met; chimeric antigen receptor; hepatocellular carcinoma; immunotherapy.

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Conflict of interest statement

The authors reported no conflict of interests.

Figures

Figure 1
Figure 1
Generation of c-Met CAR-T cells.
Figure 2
Figure 2
c-Met CAR-T cells recognize and kill c-Met-positive HCC cells.
Figure 2
Figure 2
Figure 3
Figure 3
c-Met CAR-T cells produced IFN-γ and IL-2 upon stimulation with HepG2 and shMet-HepG2 cells.
Figure 4
Figure 4
Anti-tumor efficacy of c-Met CAR-T cells in human HCC xenograft model.
Figure 5
Figure 5
H&E and immunohistochemistry staining of the tumor tissues.
See this image and copyright information in PMC

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