# Ribas and Wolchok 2018: cancer immunotherapy using checkpoint blockade

Source: https://onco.cc/key-papers/paper-ribas-wolchok-checkpoint-blockade-science-2018/  
OnCo record `paper-ribas-wolchok-checkpoint-blockade-science-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A review by two of the field's leading trialists, written as checkpoint inhibitors reached a dozen cancers, explaining how CTLA-4 and PD-1 blockade work, why only some patients respond, and how resistance arises.

## Summary

Ribas and Wolchok summarised the science and clinical results of checkpoint blockade at the point where PD-1 pathway antibodies had been approved across many cancers. They described CTLA-4 blockade as broadening the T cell repertoire and PD-1 blockade as reinvigorating exhausted T cells already in the tumour; reviewed the features of responding tumours, including mutational burden, pre-existing T cell infiltration and interferon-gamma signalling; and catalogued primary and acquired resistance mechanisms such as loss of antigen presentation and interferon signalling defects. They argued for rational combinations based on these mechanisms.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Science
- Year: 2018
- DOI: 10.1126/science.aar4060
- Authors: Ribas A, Wolchok JD.
- Findings: CTLA-4 blockade acts mainly at T cell priming and broadens the repertoire; PD-1 blockade reinvigorates antigen-experienced T cells in the tumour.; Response is associated with mutational burden, pre-existing T cell infiltration and intact interferon-gamma signalling.; Resistance arises through loss of antigen presentation (for example beta-2-microglobulin), JAK-STAT defects and immunosuppressive microenvironments.
- What it means: This is the standard overview of checkpoint immunotherapy for clinicians and scientists, tying together the trial results and the biology of response and resistance that guide today's combination trials.
- Caveats: A review; the field has moved on with LAG-3 blockade, neoadjuvant use and new biomarkers.; Both authors led many of the trials discussed.

## Sources

- Full text (DOI): https://doi.org/10.1126/science.aar4060

## Connected records

- key papers: [Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy](https://onco.cc/key-papers/paper-pardoll-immune-checkpoint-blockade-nrc-2012/), [Tumeh 2014: PD-1 blockade works by releasing T cells already present at the tumour edge](https://onco.cc/key-papers/paper-tumeh-pd1-adaptive-immune-resistance-nature-2014/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [CTLA-4](https://onco.cc/targets/ctla4/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/), [UCLA Jonsson Comprehensive Cancer Center](https://onco.cc/institutions/ucla-jonsson/)
- terms: [Immune checkpoint](https://onco.cc/terms/immune-checkpoint/), [Immune-related adverse events (irAEs)](https://onco.cc/terms/irae/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- people: [Antoni Ribas](https://onco.cc/people/antoni-ribas/), [Jedd D. Wolchok](https://onco.cc/people/jedd-wolchok/)

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