# Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy

Source: https://onco.cc/key-papers/paper-pardoll-immune-checkpoint-blockade-nrc-2012/  
OnCo record `paper-pardoll-immune-checkpoint-blockade-nrc-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The review that named and organised the field of checkpoint blockade: tumours switch off attacking T cells through brakes such as CTLA-4 and PD-1, and antibodies that release those brakes can produce lasting responses.

## Summary

Written as the first PD-1 antibody results appeared, Pardoll's review explained how immune checkpoints, receptors that normally protect tissues from autoimmunity, are exploited by tumours, and why blocking them is a fundamentally different approach from vaccines or cytokines. It contrasted CTLA-4, which acts early in lymph nodes, with PD-1 and its ligand PD-L1, which act in the tumour itself, catalogued further checkpoints such as LAG-3 and TIM-3, and set out the questions that have shaped the decade since: biomarkers, combinations, and the autoimmune side effects that come with releasing the brakes.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Nature Reviews Cancer
- Year: 2012
- DOI: 10.1038/nrc3239
- Authors: Pardoll DM.
- Findings: Immune checkpoints are inhibitory receptors on T cells that tumours co-opt; CTLA-4 acts mainly during T cell priming and PD-1 during the effector phase in tissues.; PD-L1 expression by tumour cells offers a mechanism-based biomarker and a rationale for anti-PD-1 and anti-PD-L1 antibodies.; Multiple additional checkpoints (LAG-3, TIM-3, BTLA, adenosine and others) offer combination targets.
- What it means: This is the most cited map of the immunotherapy revolution and a good first read before the trials. Its predictions largely held: PD-1 pathway antibodies became the most widely used cancer drugs, PD-L1 testing entered practice, and LAG-3 blockade was approved in melanoma a decade later.
- Caveats: A review written before most phase 3 evidence existed.; Biomarkers for checkpoint blockade remain imperfect despite the mechanistic case for PD-L1.

## Sources

- Full text (DOI): https://doi.org/10.1038/nrc3239

## Connected records

- key papers: [Chen and Mellman 2013: the cancer-immunity cycle](https://onco.cc/key-papers/paper-chen-mellman-cancer-immunity-cycle-immunity-2013/), [Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma](https://onco.cc/key-papers/paper-hodi-ipilimumab-melanoma-nejm-2010/), [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/), [Schreiber, Old and Smyth 2011: cancer immunoediting](https://onco.cc/key-papers/paper-schreiber-cancer-immunoediting-science-2011/), [Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer](https://onco.cc/key-papers/paper-topalian-anti-pd1-nejm-2012/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [CTLA-4](https://onco.cc/targets/ctla4/), [LAG-3](https://onco.cc/targets/lag3/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/), [TIM-3](https://onco.cc/targets/tim3/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- terms: [Immune checkpoint](https://onco.cc/terms/immune-checkpoint/), [Immune surveillance and cancer immunoediting](https://onco.cc/terms/immune-surveillance-immunoediting/), [Immune-related adverse events (irAEs)](https://onco.cc/terms/irae/)
- people: [Drew M. Pardoll](https://onco.cc/people/drew-pardoll/)

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