Precursor exhausted T cells: key to successful immunotherapy?

Recent studies have revealed a specialized population of 'exhausted' CD8(+) T cells that expands on immune checkpoint blockade therapy for cancer and may explain how T cell responses are maintained in chronic conditions. Here, the authors describe their phenotypic, developmental and functional characteristics and why they should be harnessed for successful immunotherapy. Cytotoxic T cell immunity in response to chronic infections and tumours is maintained by a specialized population of CD8(+) T cells that exhibit hallmarks of both exhausted and memory cells and give rise to terminally differentiated exhausted effector cells that contribute to viral or tumour control. Importantly, recent work suggests these cells, which we refer to as 'precursor exhausted' T (T-PEX) cells, are responsible for the proliferative burst that generates effector T cells in response to immune checkpoint blockade targeting programmed cell death 1 (PD1), and increased T-PEX cell frequencies have recently been linked to increased patient survival. We believe the recent discovery of T-PEX cells not only represents a paradigm shift in our understanding of the mechanisms that maintain CD8(+) T cell responses in chronic infections and tumours but also opens up unexpected avenues for the development of new and innovative therapeutic approaches. In this Opinion article, we discuss the differentiation and function of T-PEX cells and suggest that targeting these cells may be key for successful immunotherapy.