Chromatin states define tumour-specific T cell dysfunction and reprogramming

Mary Philip, Lauren Fairchild, Liping Sun, Ellen L. Horste, Steven Camara, Mojdeh Shakiba, Andrew C. Scott, Agnes Viale, Peter Lauer, Taha Merghoub, Matthew D. Hellmann, Jedd D. Wolchok, Christina S. Leslie and Andrea Schietinger ()
Additional contact information
Mary Philip: Immunology Program, Memorial Sloan Kettering Cancer Center
Lauren Fairchild: Computational Biology Program, Memorial Sloan Kettering Cancer Center
Liping Sun: Integrated Genomics Operation, Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center
Ellen L. Horste: Immunology Program, Memorial Sloan Kettering Cancer Center
Steven Camara: Immunology Program, Memorial Sloan Kettering Cancer Center
Mojdeh Shakiba: Immunology Program, Memorial Sloan Kettering Cancer Center
Andrew C. Scott: Immunology Program, Memorial Sloan Kettering Cancer Center
Agnes Viale: Integrated Genomics Operation, Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center
Peter Lauer: Aduro Biotech, Inc.
Taha Merghoub: Weill Cornell Medical College, Cornell University
Matthew D. Hellmann: Weill Cornell Medical College, Cornell University
Jedd D. Wolchok: Weill Cornell Medical College, Cornell University
Christina S. Leslie: Computational Biology Program, Memorial Sloan Kettering Cancer Center
Andrea Schietinger: Immunology Program, Memorial Sloan Kettering Cancer Center

Nature, 2017, vol. 545, issue 7655, 452-456

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22367

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