Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack
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.
- PD-L1 expression on tumour cells reduced cytotoxic T-cell killing in vitro and enhanced tumour growth in mice
- Anti-PD-L1 antibody suppressed growth of PD-L1-expressing tumours
- Naturally PD-L1-positive myeloma cells were rejected in PD-1-deficient mice but not in wild-type mice
- Together with Ishida 1992 and Freeman 2000, defined the PD-1/PD-L1 axis as a tumour immune-escape mechanism
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.
- Mouse tumour models overexpressing PD-L1 exaggerate a mechanism that is only one of many in human tumours
- PD-L1 expression on tumour cells is an imperfect biomarker of response in patients
- Most patients do not respond to PD-1 blockade, and mechanisms of primary resistance remain incompletely understood
- Clinical translation took another decade and depended on industry (Ono, Medarex, BMS, Merck) investment