期刊
ONCOIMMUNOLOGY
卷 10, 期 1, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2021.1901434
关键词
Gastric Cancer; car-T; c-Met; pd1; CD28; immunotherapy
资金
- National Natural Science Foundation of China [31770537, 81972523, 81870329, 81960673]
- Key Research and Development Project of Gansu Science and Technology Plan [18YF1WA113]
- Talent Innovation and Entrepreneurship Project of Lanzhou City [2020-RC-38, 2017-RC-1]
- China Scholarship Council [201806180088]
This study found an increased expression of c-Met in gastric cancer. Experiments with different CAR-T cells showed that PD1/CD28 CSR can enhance the killing ability of c-Met CAR-T and reduce the release level of IL-6, with no obvious off-target toxicity to normal tissues.
Chimeric antigen receptor (CAR) T cell is a promising method in cancer immunotherapy but faces many challenges in solid tumors. One of the major problems was immunosuppression caused by PD-1. In our study, the expression of c-Met in GC was analyzed from TCGA datasets, GC tissues, and cell lines. The c-Met CAR was a second-generation CAR with 4-1BB, cMet-PD1/CD28 CAR was c-Met CAR adding PD1/CD28 chimeric-switch receptor (CSR). In vitro, we measured the changes of different subgroups, phenotypes and PD-1 expression in CAR-T cells. We detected the secretion levels of different cytokines and the killing ability of CAR-Ts. In vivo, we established a xenograft GC model and observed the anti-tumor effect and off-target toxicity of different CAR-Ts. We find that the expression of c-Met was increased in GC. CD3(+)CD8(+) T cells and CD62L(+)CCR7(+) central memory T cells (T-CM) were increased in two CAR-Ts. The stimulation of target cells could promote the expression of PD-1 in c-Met CAR-T. Compared with Mock T, the secretion of cytokines as IFN-gamma, TNF-alpha, IL-6, IL-10 secreted by two CAR-Ts was increased, and the killing ability to c-Met positive GC cells was enhanced. The PD1/CD28 CSR could further enhance the killing ability, especially the long-term anti-tumor effect of c-Met CAR-T, and reduce the release level of IL-6. CAR-Ts target c-Met had no obvious off-target toxicity to normal organs. Thus, the PD1/CD28 CSR could further enhance the anti-tumor ability of c-Met CAR-T, and provides a promising design strategy to improve the efficacy of CAR-T in GC.
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