Recently, the research team of Li Peng, a researcher at the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences, published a study titled Co-expression of a PD-L1-specific chimeric switch receptor augments the efficiency and persistence of CAR T cells via the CD70-CD27 axis in "Nature communications", providing a new strategy for enhancing the anti-tumor activity of CAR-T cell therapy.
In recent years, chimeric antigen receptor T (CAR-T) cell therapy has achieved breakthrough results in the field of hematologic malignant tumors, but its efficacy in solid tumor patients is still not ideal. Solid tumor cells express inhibitory molecules such as PD-L1, which binds to PD-1 on the surface of CAR-T cells, resulting in the inhibition of CAR-T cell function, which is one of the important reasons for the poor efficacy of CAR-T cells in patients with solid tumors. In view of this, there have been studies that co-express the chimeric switching receptor (CSR) targeting PD-L1 in CAR-T cells, aiming to convert the inhibitory signal of PD-L1 on CAR-T cells into activation signals and enhance the anti-tumor activity of CAR-T cells. However, in addition to being expressed in solid tumor cells and on the surface of activated CAR-T cells, the effect of PD-L1 on the anti-tumor activity of CAR-T cells after CSR trans-binding activation targeting PD-L1 is not yet clear.
research team designed CSR molecule CARP targeting PD-L1, which does not contain CD3ζ chain, so CARP-T cells do not have tumor killing activity. Research has proved in vitro and in tumor humanized mouse models that CARP-T cells can enhance the anti-tumor activity of CAR-T cells, promote the differentiation of central memory-like CAR-T cells, and reduce the secretion of Th2 cytokines such as IL5, IL10 and IL13 in CAR-T cells. Related mechanism studies have found that CARP molecules can trans-bound PD-L1 on the surface of CAR-T cells, causing connections between CARP-T cells and CAR-T cells. Single-cell RNA sequencing found that the connection between CARP-T cells and CAR-T cells promotes the communication between CD70 and CD27 molecules between the two cells, while the CD70-CD27 signaling pathway further promotes the differentiation of central memory-like CAR-T cells and reduces the secretion of Th2 cytokines, ultimately improving the anti-tumor activity of CAR-T cells. In addition, studies have found that such cell-to-cell communication is not limited to CSR-T cells targeting PD-L1, and CSR-T cells targeting CD19 can also enhance the anti-tumor activity of CAR-T cells co-expressing CD19 molecules. Studies have shown that CSR molecules trans-bound CAR-T cell surface target antigens can improve the efficacy and durability of CAR-T cells through the CD70-CD27 signaling pathway. At present, the research is in the basic research stage.
research work has been supported by the National Key R&D Plan, National Natural Science Foundation of , Guangdong Province, etc.
CSR-T cells targeting CAR-T cells surface antigen enhance CAR-T cells through CD70-CD27 signaling pathway concept diagram
Source: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences
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