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Recently, the research group of researcher Li Peng of the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences published a report in Nature communications Co-expression of a PD-L1-specific chimeric switch receptor augments the efficacy and persistence of CAR T cells via the CD70-CD27 axis, for Enhancing the anti-tumor activity of CAR-T cell therapy provides a new strategy
.
.
In recent years, chimeric antigen receptor T (CAR-T) cell therapy has achieved breakthrough efficacy in the field of hematological malignancies, but its efficacy in patients with solid tumors is still not ideal
。 Solid tumor cells express inhibitory molecules such as PD-L1, which bind to PD-1 on the surface of CAR-T cells, and ultimately inhibit the function of CAR-T cells, which is one of the important reasons for the poor efficacy of CAR-T cells in patients with solid tumors
。 In view of this, multiple research groups subsequently co-expressed a chimeric conversion receptor (CSR) targeting PD-L1 in CAR-T cells, aiming to convert the inhibitory signal of PD-L1 to CAR-T cells into an activation signal And finally effectively improve the anti-tumor activity
of CAR-T cells.
However, PD-L1 is not only expressed in solid tumor cells, but also on the surface of activated CAR-T cells, and the effect of PD-L1 on the anti-tumor activity of CAR-T cells after the activation of CSR trans-binding targeting PD-L1 is still unclear
。
。 Solid tumor cells express inhibitory molecules such as PD-L1, which bind to PD-1 on the surface of CAR-T cells, and ultimately inhibit the function of CAR-T cells, which is one of the important reasons for the poor efficacy of CAR-T cells in patients with solid tumors
。 In view of this, multiple research groups subsequently co-expressed a chimeric conversion receptor (CSR) targeting PD-L1 in CAR-T cells, aiming to convert the inhibitory signal of PD-L1 to CAR-T cells into an activation signal And finally effectively improve the anti-tumor activity
of CAR-T cells.
However, PD-L1 is not only expressed in solid tumor cells, but also on the surface of activated CAR-T cells, and the effect of PD-L1 on the anti-tumor activity of CAR-T cells after the activation of CSR trans-binding targeting PD-L1 is still unclear
。
The research team first designed the CSR molecule CARP targeting PD-L1, because it does not contain CD3ζ chain, CARP-T cells do not have tumor-killing activity
.
Subsequently, the research team demonstrated in vitro and tumor humanized mouse models that CARP-T cells can enhance the anti-tumor activity of CAR-T cells and promote central memory-like CAR-T Cell differentiation, while reducing the secretion
of Th2 cytokines such as IL5, IL10 and IL13 in CAR-T cells.
Related mechanism studies have found that CARP molecules can activate PD-L1 on the surface of CAR-T cells by trans-binding, resulting in the connection between CARP-T cells and CAR-T cells
。 Single-cell RNA sequencing found that the connection between CARP-T cells and CAR-T cells promoted the exchange of CD70 and CD27 molecules between the two cells The CD70-CD27 signaling pathway further promotes the differentiation of central memory-like CAR-T cells and reduces the secretion of Th 2 cytokines, which is ultimately improved Antitumor activity
of CAR-T cells.
In addition, the research team 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 the CD19 molecule
。 The results show that CSR molecules can improve the efficacy and persistence
of CAR-T cells through the CD70-CD27 signaling pathway after trans-binding to the target antigen on the surface of CAR-T cells.
The research work was mainly completed by Dr.
Qin Le of Guangzhou Health Institute, with researcher Li Peng of Guangzhou Health Center and Jean Paul Thiery of Guangzhou Laboratory as the corresponding author
of this paper.
The research results have been supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, and the major new drug development of Guangdong Province.
Conceptual diagram of CSR-T cells targeting CAR-T cell surface antigen to enhance antitumor activity of CAR-T cells through CD 70-CD 27 signaling pathway
Links to papers
