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Nature. 2017 May 25;545(7655):452-456. doi: 10.1038/nature22367. Epub 2017 May 17.

Chromatin states define tumour-specific T cell dysfunction and reprogramming.

Author information

1
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
2
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
3
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
4
Integrated Genomics Operation, Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
5
Weill Cornell Medical College, Cornell University, New York, New York 10065, USA.
6
Aduro Biotech, Inc., Berkeley, California 94720, USA.
7
Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
8
Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
9
Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Abstract

Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.

PMID:
28514453
PMCID:
PMC5693219
DOI:
10.1038/nature22367
[Indexed for MEDLINE]
Free PMC Article

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