# Tumeh 2014: PD-1 blockade works by releasing T cells already present at the tumour edge

Source: https://onco.cc/key-papers/paper-tumeh-pd1-adaptive-immune-resistance-nature-2014/  
OnCo record `paper-tumeh-pd1-adaptive-immune-resistance-nature-2014` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Melanomas that responded to pembrolizumab already contained killer T cells pressed up against tumour cells expressing PD-L1, showing that the drug works by releasing an immune attack that is already there rather than creating a new one.

## Summary

Tumeh, Ribas and colleagues at UCLA studied tumour biopsies from 46 patients with metastatic melanoma before and during pembrolizumab. Responding tumours had higher densities of CD8 T cells, PD-1 and PD-L1 at the invasive margin and in the tumour before treatment, with T cells and PD-L1 in close proximity, and their T cell receptor repertoires were more clonal and expanded further on treatment. The authors proposed that PD-L1 is induced as an adaptive resistance mechanism in response to interferon from attacking T cells and that pembrolizumab reverses it.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Nature
- Year: 2014
- DOI: 10.1038/nature13954
- Authors: Tumeh PC, Harview CL, Yearley JH, et al.
- Findings: Serial biopsies from 46 melanoma patients treated with pembrolizumab.; Pre-treatment CD8 T cell density and PD-1 and PD-L1 expression at the invasive margin and in the tumour were higher in responders.; Responders showed more clonal T cell receptor repertoires that expanded during treatment.; A predictive model based on these features identified most responders in a validation set.
- What it means: This paper explained why PD-1 antibodies work in some patients and not others and introduced the idea of inflamed versus non-inflamed tumours that now guides combination strategies designed to bring T cells into cold tumours.
- Caveats: Small cohort from a single centre.; Biopsies sample one site and may not represent all metastases.

## Sources

- Full text (DOI): https://doi.org/10.1038/nature13954

## Connected records

- key papers: [Binnewies 2018: understanding the tumour immune microenvironment for effective therapy](https://onco.cc/key-papers/paper-binnewies-tumor-immune-microenvironment-natmed-2018/), [Ribas and Wolchok 2018: cancer immunotherapy using checkpoint blockade](https://onco.cc/key-papers/paper-ribas-wolchok-checkpoint-blockade-science-2018/), [Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer](https://onco.cc/key-papers/paper-rizvi-mutational-landscape-pd1-science-2015/)
- cancers: [Melanoma](https://onco.cc/cancers/melanoma/)
- targets: [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- institutions: [UCLA Jonsson Comprehensive Cancer Center](https://onco.cc/institutions/ucla-jonsson/)
- terms: [Immune checkpoint](https://onco.cc/terms/immune-checkpoint/), [Tumour-infiltrating lymphocytes (TILs)](https://onco.cc/terms/tils/)
- people: [Antoni Ribas](https://onco.cc/people/antoni-ribas/)

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