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A decade after Honjo's group cloned PD-1 (1992), this study showed that tumour cells expressing PD-L1 resist killing by cytotoxic T cells in mice, and that anti-PD-L1 antibody or PD-1 deficiency restores tumour rejection, the foundation of PD-1/PD-L1 therapy.
Tasuku Honjo's group discovered PD-1 in 1992 (Ishida et al., EMBO J) as a gene induced during programmed cell death in T-cell lines, and later showed PD-1-deficient mice develop autoimmunity, identifying it as an inhibitory receptor. PD-L1 (B7-H1) was identified as its ligand by Freeman, Honjo and colleagues in 2000.
In this paper, P815 mastocytoma cells transfected with PD-L1 were less susceptible to lysis by cytotoxic T lymphocytes in vitro and grew more aggressively in vivo; anti-PD-L1 antibody reversed this. Myeloma cells naturally expressing PD-L1 grew in wild-type mice but were rejected in PD-1-deficient mice. In parallel, Dong and Chen (Nature Medicine 2002) showed that PD-L1 expressed on human tumours induced T-cell apoptosis.
These data motivated the development of nivolumab (Ono/Medarex) and other PD-1 and PD-L1 antibodies, now the most widely used cancer drugs in the world. Honjo shared the 2018 Nobel Prize with James Allison.
Tumours hide from T cells by displaying PD-L1; blocking that interaction lets the immune system attack. This is the mechanism of pembrolizumab, nivolumab, atezolizumab and their relatives, which now treat more than 20 cancer types.
Shares James P. Allison, No one can predict who responds to immunotherapy, PD-L1, Nivolumab.
Shares Lieping Chen, Drew M. Pardoll, No one can predict who responds to immunotherapy, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares Atezolizumab, PD-L1, PD-1, Pembrolizumab.
Shares PD-1 / PD-L1 immune checkpoint & T-cell activation, PD-L1, Nivolumab, PD-1.
Shares Drew M. Pardoll, Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours, James P. Allison, Antigen presentation & immune editing.
Shares No one can predict who responds to immunotherapy, PD-1 / PD-L1 immune checkpoint & T-cell activation, Atezolizumab, Biomarkers are not validated or standardised.
Shares No one can predict who responds to immunotherapy, Biomarkers are not validated or standardised, PD-L1, Pembrolizumab.
Shares Antigen presentation & immune editing, PD-1 / PD-L1 immune checkpoint & T-cell activation, Nivolumab, Pembrolizumab.