Nature
Nature
5 years ago

Chromatin states define tumour-specific T cell dysfunction and reprogramming

Chromatin states define tumour-specific T cell dysfunction and reprogramming
Lauren Fairchild, Agnes Viale, Matthew D. Hellmann, Mojdeh Shakiba, Liping Sun, Christina S. Leslie, Peter Lauer, Andrea Schietinger, Andrew C. Scott, Taha Merghoub, Mary Philip, Ellen L. Horste, Jedd D. Wolchok, Steven Camara
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.

Publisher URL: http://dx.doi.org/10.1038/nature22367

DOI: 10.1038/nature22367

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