The epigenetic landscape of T cell exhaustion

By Debattama R. Sen, James Kaminski, R. A. Barnitz, M. Kurachi, U. Gerdemann, Kathleen B. Yates, Hsiao-Wei Tsao, Jernej Godec, M. LaFleur, Flavian D. Brown and 9 more. Science, 2016

868 citations recorded by the source corpus.

Epigenetic profiling suggests that exhausted T cells are a distinct cell linage. The epigenetics of exhaustion During cancer or chronic infection, T cells become dysfunctional, eventually acquiring an “exhausted” phenotype. Immunotherapies aim to reverse this state. Using a mouse model of chronic infection, two studies now show that the epigenetic profile of exhausted T cells differs substantially from those of effector and memory T cells, suggesting that exhausted T cells are a distinct lineage (see the Perspective by Turner and Russ). Sen et al. defined specific functional modules of enhancers that are also conserved in exhausted human T cells. Pauken et al. examined the epigenetic profile of exhausted T cells after immunotherapy. Although there was transcriptional rewiring, the cells never acquired a memory T cell phenotype. Thus, epigenetic regulation may limit the success of immunotherapies. Science, this issue p. 1104, p. 1165; see also p. 1160 Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/cd7e960f3e4420b8c714d9fc5ca0ff2ab849018a

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Citations in the corpus

The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “Exhausted human and mouse T cells have sustained expression of PD-1 that is regulated by an exhaustionspecific enhancer that contains motifs from RAR, T-bet, and Sox3 (Sen et al., 2016), and the stability of the epigenetic changes leads to resistance to PD-1 antagonists (Pauken et al., 2016).”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Tex cells differ from other CD8 T cells by ∼6,000 differentially accessible chromatin regions (42, 43), consistent with the scale of difference between other distinct hematopoietic lineages (124, 125).”
Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “Exhausted PD-1þ CD8þ T cells display a distinct chromatin landscape compared with effector T cells and TEM cells (Pauken et al, 2016; Sen et al, 2016), and these epigenetically distinct T-cell states influence whether or not exhausted PD-1þ T cells can be reprogrammed to avoid terminal exhaustion…”
Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. (2017, positive): “Although the clinical efficacy of various checkpoint inhibitors hinges at least in part upon their ability to unleash the CD8 cytotoxic T cells in the tumor microenvironment, the cytotoxic activity of these T cells could be rendered ineffective primarily by the suppression of Tregs (Nishikawa and Sa”
Pan-cancer single-cell landscape of tumor-infiltrating T cells (2021, background): “Intrinsically, T cell exhaustion appears to be tightly regulated by several transcription factors (TFs), including TOX (thymocyte selection-associated high mobility group box) (4, 5) and TCF7 (transcription factor 7) (6), as well as epigenetic regulators that shape the specific state observed in dys”