Abstract
T-cell exhaustion was a four-stage process; the transition to terminal exhaustion was irreversible.
Major Finding: T-cell exhaustion was a four-stage process; the transition to terminal exhaustion was irreversible.
Concept: Each stage was unique in its epigenetic landscape, transcriptomic signature, and anatomic location.
Impact: Understanding the phases of T-cell exhaustion may help develop strategies to prevent or reverse it.
CD8+ T-cell exhaustion due to chronic antigen exposure dampens the potential efficacy of immunotherapies for cancer, necessitating study of how T-cell exhaustion develops. Beltra and colleagues found four subsets of exhausted T cells in vivo that were defined by their expression of the cell-surface receptor LY108 (SLAMF6 in humans) and the transmembrane C-type lectin CD69. These four exhausted T-cell subsets fell into a developmental hierarchy: LY108+CD69+ (termed progenitor 1) cells interconverted with LY108+CD69− (termed progenitor 2) cells, progenitor 2 cells underwent a reversible proliferation-driven transition to LY108−CD69− (termed intermediate) cells, and intermediate cells underwent an irreversible transition to LY108−CD69+ (termed terminal) cells. The exhausted T-cell types differed in their anatomic locations, with progenitor 1 cells residing in the spleen's white pulp, progenitor 2 cells and intermediate cells circulating in the blood, and terminal cells residing in the spleen's red pulp and peripheral tissues. Each type also exhibited a unique transcriptomic signature, the characteristics of which provided further evidence for the stepwise transitions between each type. Investigation of the epigenetic lanscape of each type also supported the observed hierarchy of exhausted T-cell types. Notably, progenitor 1 and progenitor 2 cells had similar open-chromatin features, but progenitor 2 cells also had some epigenetic characteristics more similar to intermediate cells, and further remodeling was apparent when comparing intermediate to terminal cells. The transition between progenitor 2 and intermediate cells was mediated by the opposing effects of the transcription factors TBET and TCF1, the former of which was essential for intermediate cell development from progressive 2 cells and the latter of which favored the reverse transition from intermediate cells back to progressive 2 cells. Consistent with its known role in driving T-cell exhaustion, the chromatin regulator TOX opposed TBET expression to promote the transition from intermediate cells to terminal cells. Together, these results support a stepwise mechanism by which CD8+ T cells progress to an exhausted phenotype, providing insights necessary to potentially prevent or reverse T-cell exhaustion in cancer.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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