Dissecting the heterogeneity of exhausted T cells at the molecular level.

Our understanding of mechanisms underlying T-cell exhaustion has been refined by analysis of exhausted T cells at the molecular level. The development and functions of exhausted T cells are regulated by a number of transcription factors, epigenetic factors and metabolic enzymes. In addition, recent work to dissect exhausted T cells at the single-cell level has enabled us to discover a precursor exhausted T-cell subset equipped with long-term survival capacity. Starting from the analysis of mouse models, the existence of precursor exhausted T cells has also been documented in human T cells in the context of chronic virus infections or tumors. Clinical data suggest that evaluating the quality of exhausted T cells on the basis of their differentiation status may be helpful to predict the therapeutic response to inhibition of programmed death 1 (PD1). Moreover, beyond immune-checkpoint blockade, novel therapeutic approaches to re-invigorate exhausted T cells have been explored based on molecular insights into T-cell exhaustion. Here I will discuss key molecular profiles associated with the development, maintenance and differentiation of exhausted T cells and how these findings can be applicable in the field of cancer immunotherapy.