Chromatin states define tumour-specific T cell dysfunction and reprogramming

Nature
Mary PhilipAndrea Schietinger

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 PD1(hi) dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1(hi) 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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Datasets Mentioned

BETA
GSE89309
GSE89308
GSE
15907
89309

Methods Mentioned

BETA
RNA-Seq
ATAC-Seq
nuclear translocation
FCS
flow cytometry
PCR
PCA
footprinting

Software Mentioned

UCSC liftOver
GraphPad
GenomicAlignments
MEME
MACS2
bnMapper
DESeq2
UCSC
bedtools
GenomicRanges

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