Article | Published:

Chromatin states define tumour-specific T cell dysfunction and reprogramming

Nature volume 545, pages 452456 (25 May 2017) | Download Citation

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.

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Acknowledgements

We thank J. van der Veeken, V. Krisnawan, Y. Pritykin, and B. Gasmi for discussions and technical support; S. Reiner for discussions; and the MSKCC Flow Cytometry Core and Animal Facility. T.M., M.H., J.D.W., and A.S. are members of the Parker Institute for Cancer Immunotherapy. This work was supported by NIH-NCI grants R00 CA172371 (to A.S.), K08 CA158069 (to M.P.), and U54 CA209975 (to C.S.L. and A.S.), NHGRI grant U01 HG007893 (to C.S.L.), V Foundation for Cancer Research (to A.S.), the William and Ella Owens Medical Research Foundation (to A.S.), the Josie Robertson Young Investigator Award (to A.S.), and the MSKCC Core Grant P30 CA008748. The Integrated Genomics Operation Core was supported by Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.

Author information

Affiliations

  1. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Mary Philip
    • , Ellen L. Horste
    • , Steven Camara
    • , Mojdeh Shakiba
    • , Andrew C. Scott
    •  & Andrea Schietinger
  2. Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Lauren Fairchild
    •  & Christina S. Leslie
  3. Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Lauren Fairchild
  4. Integrated Genomics Operation, Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Liping Sun
    •  & Agnes Viale
  5. Weill Cornell Medical College, Cornell University, New York, New York 10065, USA

    • Mojdeh Shakiba
    • , Andrew C. Scott
    • , Taha Merghoub
    • , Matthew D. Hellmann
    • , Jedd D. Wolchok
    •  & Andrea Schietinger
  6. Aduro Biotech, Inc., Berkeley, California 94720, USA

    • Peter Lauer
  7. Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Taha Merghoub
    •  & Jedd D. Wolchok
  8. Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Matthew D. Hellmann
  9. Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Jedd D. Wolchok

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Contributions

M.P. and A.S. conceived and designed the study, carried out experiments, and analysed and interpreted data. L.F. designed and performed all high-throughput computational analyses; C.S.L. designed and supervised computational analyses; E.H., S.C., M.S., and A.C.S. assisted with experiments; L.S. and A.V. performed ATAC-seq; P.L. generated Listeria strains; and T.M., M.H., and J.D.W. provided human samples. M.P. and A.S. wrote the manuscript, with all authors contributing to writing and providing feedback.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andrea Schietinger.

Reviewer Information Nature thanks J. Wherry and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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https://doi.org/10.1038/nature22367

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