# Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack

Source: https://onco.cc/key-papers/paper-iwai-pdl1-tumour-escape-pnas-2002/  
OnCo record `paper-iwai-pdl1-tumour-escape-pnas-2002` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: PNAS
- Year: 2002
- DOI: 10.1073/pnas.192461099
- Authors: Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N
- Findings: 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
- What it means: 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.
- Caveats: 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

## Sources

- DOI: https://doi.org/10.1073/pnas.192461099
- Discovery of PD-1 (Ishida 1992): https://doi.org/10.1002/j.1460-2075.1992.tb05481.x

## Connected records

- key papers: [Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours](https://onco.cc/key-papers/paper-leach-allison-ctla4-blockade-science-1996/)
- fronts: [Immunotherapy](https://onco.cc/fronts/immunotherapy/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/)
- people: [Drew M. Pardoll](https://onco.cc/people/drew-pardoll/), [James P. Allison](https://onco.cc/people/james-allison/), [Lieping Chen](https://onco.cc/people/lieping-chen/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/)
- journals: [Proceedings of the National Academy of Sciences](https://onco.cc/journals/pnas/)

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