Programmed Death Ligand 1 (PD-L1, also known as B7-H1) is an immune checkpoint expressed on the surface of tumor cells or on the surface of host immune cells adjacent to the tumor microenvironment. PD-L1 binds to the PD-1 receptor expressed on the surface of T lymphocytes and transmits an inhibitory second signal, thus inhibiting the activation of T cells or other immune cells. Because T lymphocytes play an important role in anti-tumor immunity by mediating the adaptive anti-tumor immunity, the high expression of PD-L1 in the tumor microenvironment can significantly inhibit the function of tumor infiltrating T cells, thereby allowing tumor cells to escape immune surveillance.
Figure 1. Simplified illustration of the complex interaction between PD-1 and PD-L1 (Hartkopf et al. 2016)
PD-L1 is widely and diversely expressed in most malignant tumors. In many cancer patients, including lung cancer, melanoma, kidney cancer and urothelial carcinoma, the inhibition of PD-L1 expression facilitates extending overall survival. The expression of PD-L1 is induced by intrinsic and extrinsic signals of tumor cells. Intrinsic signal: PD-L1 expression can be promoted by the activation of protein kinase B (PKB), signal transducer and activator of transcription 3 (STAT3), KRAS and EGFR signaling pathways. Besides the constitutive expression of PD-L1 with the presence of tumor cell intrinsic signals, PD-L1 expression can also be induced by extrinsic signals Interferon-c secreted by the infiltrated immune cells was required for PD-L1 induction. Three humanized monoclonal antibodies, Atezolizumab (MPDL3280A), Avelumab (MSB0010718C), and Durvalumab (MEDI4736), bind to PD-L1 and have shown significant therapeutic effects in clinical trials.
Humanized PD-L1 mouse
Figure 2. Generation strategy of humanized PD-L1 mice. On the C57BL/6J genetic background, the protein coding sequences for human PD-L1 were inserted into the ATG position of the mouse Pd-l1 gene, so that the expression of endogenous Pd-l1 in the mouse was replaced by the expression of fully humanized PD-L1 protein.
Figure 3. Expression of PD-L1 in the spleen lymphocytes collected from homozygous humanized PD-L1 mice and wild-type mice is detected by FACS.
The results showed that the expression of human PD-L1 can be detected in both T cells and B cells collected from the spleen of homozygous humanized PD-L1 mice. (Completed in collaboration with CrownBio)
Figure 4. In vivo validation of anti-tumor efficacy in a MC38 tumor-bearing model of humanized PD-L1 mice. Homozygous humanized PD-L1 mice were inoculated with MC38 colon cancer cells (expressing human PDL1 rather than murine PD-L1). After the tumors grew to 100 mm3, the animals were randomly assigned into a control group and a treatment group (n=5). The results showed: The antibodies targeting human PD-L1 were associated with a very significant anti-tumor effect (TGI: tumor growth inhibition, p < 0.001), demonstrating that the humanized PD-L1 mice are a good in vivo model for validating the efficacy of antibodies targeting human PD-L1.
Know More Humanized Mouse Models
1.Xu W, Jiang H, Gao J, et al. (2014) “The upregulation of immune checkpoint ligand PD-L1 in tumour microenvironment.” Scand J Immunol 80(1):71-72. doi: 10.1111/sji.12177.
2.Hartkopf A D, Taran F A, Wallwiener M, et al. (2016) “PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer.” Breast Care 11:385-390.
3.Al-Ahmadie H (2016) “PD-L1 expression in penile cancer: a new frontier for immune checkpoint inhibitors?” Ann Oncol 27 (9): 1658-1659.