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Published on: May 14, 2021
Targeting fibroblast activation protein with chimeric antigen receptor macrophages
Yizhi Mao1, Chen Yao1, Shimeng Zhang1
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
Abstract:
Under the rapid advancement of chimeric antigen receptor T cell (CAR-T) technology, CAR-macrophages (CAR-Ms) are also being developed currently in the pre-clinical stage and have been shown to inhibit tumor growth in several mouse tumor models. Fibroblast activation protein (FAP) is a type II transmembrane serine protease, which is expressed in stromal fibroblasts of over 90 % of common human epithelial cancers and is upregulated in fibrotic diseases of the liver, lung and colon, etc. In this study, we firstly constructed FAP-CAR macrophages to target FAP+ cells through in vitro phagocytosis assays. In subsequent in vivo assays, we discovered that FAP-CAR-ΔZETA bone marrow-derived macrophages (BMDMs) rather than FAP-CAR BMDMs, exhibited a pronounced anti-tumor effect in mouse subcutaneous MC38 colon cancer model. In addition, FAP-CAR and FAP-CAR-ΔZETA BMDMs therapy could effectively improve CCl4-induced liver fibrosis in mice. Collectively, CAR-Ms targeting FAP demonstrated great therapeutic potential in cancer and liver fibrosis therapy.
Insights
Engineered macrophages targeting fibroblast activation protein (FAP) show promise for treating cancer and liver fibrosis. FAP-CAR-ΔZETA macrophages demonstrated significant anti-tumor effects and improved liver fibrosis in mouse models.
Area of Science:
- Immunotherapy
- Cellular Engineering
- Oncology
- Hepatology
Background:
- Chimeric antigen receptor T cell (CAR-T) technology is advancing rapidly.
- CAR-macrophages (CAR-Ms) are emerging as a new therapeutic strategy in pre-clinical stages.
- Fibroblast activation protein (FAP) is highly expressed in various cancers and fibrotic diseases.
Purpose of the Study:
- To construct FAP-targeted CAR macrophages (CAR-Ms).
- To evaluate the therapeutic potential of FAP-CAR-Ms in cancer and liver fibrosis models.
Main Methods:
- Constructed FAP-CAR macrophages for targeting FAP+ cells.
- Conducted in vitro phagocytosis assays.
- Performed in vivo studies using mouse subcutaneous MC38 colon cancer and CCl4-induced liver fibrosis models.
Main Results:
- FAP-CAR-ΔZETA bone marrow-derived macrophages (BMDMs) showed a pronounced anti-tumor effect in a mouse colon cancer model.
- Both FAP-CAR and FAP-CAR-ΔZETA BMDMs therapy improved CCl4-induced liver fibrosis in mice.
- FAP-CAR-Ms demonstrated efficacy in both cancer and liver fibrosis models.
Conclusions:
- FAP-CAR-Ms are a promising cellular therapy for FAP-expressing cancers.
- FAP-CAR-Ms also show therapeutic potential for fibrotic diseases like liver fibrosis.
- The FAP-CAR-ΔZETA construct exhibited superior anti-tumor activity compared to FAP-CAR in the tested model.
