On April 12th, researchers from the School of Medicine at Fudan University in Shanghai, led by Dr. Xujie, discovered the first ligand of CD3, CD3L1 (or ITPRIP L1), revealing its crucial role in tumor immune evasion and testicular immune privilege. This discovery signifies CD3L1 as a novel target for cancer immunotherapy, holding promise for breakthroughs in tumor immune treatment. The related research has been published in Cell.
The research team found that CD3L1 is consistently highly expressed in tumors lacking PD-L1 expression, and it is also expressed in immune privileged organs like PD-L1. Using single-cell sequencing, they discovered that CD3L1 can inhibit T cells. After knocking out CD3L1, mice developed autoimmune reactions in the testes, and tumor cells were more easily eliminated by T cells in the absence of CD3L1. Further investigation revealed that CD3L1 can directly bind to CD3ε, leading to continuous binding of Nck to the intracellular domain of CD3ε, competitively inhibiting the recruitment and phosphorylation of Zap70, thereby inhibiting T cell activation.
The mechanism of action of CD3L1 and its antibody. Image source: Cell.
For the first time, research teams have revealed the presence of the natural ligand of CD3 and developed a novel class of checkpoint inhibitors based on the CD3L1:CD3 immune checkpoint signaling axis, represented by CD3L1 antibody. Validation in multiple mouse tumor models showed that CD3L1 antibody can activate T cells and inhibit tumor growth, demonstrating significant therapeutic efficacy in the treatment of spontaneous pet tumors. Currently, clinical trials of CD3L1 antibody for tumor treatment have successfully obtained Investigational New Drug (IND) approval from the US FDA and China's NMPA and are in Phase I clinical research stage.
Reference: https://doi.org/10.1016/j.cell.2024.03.019
