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Nat Commun. 2016 Feb 17;7:10501. doi: 10.1038/ncomms10501.

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.

Author information

1
Department of Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
2
Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
3
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
4
Department of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
5
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
6
Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
7
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
8
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
9
Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
10
Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

Abstract

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.

Comment in

PMID:
26883990
PMCID:
PMC4757784
DOI:
10.1038/ncomms10501
[Indexed for MEDLINE]
Free PMC Article
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