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- Title
Dual CAR-T cells to treat cancers co-expressing NKG2D and PD1 ligands in xenograft models of peritoneal metastasis.
- Authors
Jiang, Guangyi; Ng, Yu Yang; Tay, Johan C. K.; Du, Zhicheng; Xiao, Lin; Wang, Shu; Zhu, Jianqing
- Abstract
While the expression of either NKG2D ligands or PD-1 ligands has been reported in various types of cancers, the co-expression of the two sets of ligands in the same tumour tissues is still un-investigated. After examining 68 primary ovarian cancer samples, we observed around 80% of the co-expression in low grade serous and endometrioid ovarian cancer samples. We then constructed a dual CAR system that splits the conventional single-input of a 2nd generation CAR into two independent chimeric receptors, one composed of the NKG2D extracellular domain linked with DAP12 for T cell activation and another using the PD-1 extracellular domain linked with 4-1BB for costimulatory signal 2 input. Given the limitation of the low-affinity PD-1 receptor in recognizing cancer cells with low levels of PD-1 ligands, we also used a high-affinity scFv specific to PD-L1 in our combinatorial approach to expand the range of target cancer cells with different expression levels of PD-L1. The two types of dual CAR-T cells were generated through electroporation of non-viral piggyBac transposon plasmids and were effective in eliminating the target cancer cells. Especially, the dual CAR-T cells with anti-PD-L1 scFv were capable of eradicating established tumors in mouse models of peritoneal metastasis of colorectal cancer and ovarian cancer. Since both NKG2D ligands and PD-1 ligands have been marked as favourable cancer therapeutic targets, the new dual CAR-T cells developed in this study hold attractive application potential in treating metastatic peritoneal carcinoma.
- Subjects
LIGANDS (Biochemistry); PROGRAMMED cell death 1 receptors; CANCER cells; OVARIAN cancer; METASTASIS
- Publication
Cancer Immunology, Immunotherapy, 2023, Vol 72, Issue 1, p223
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-022-03247-9