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 (TPEX) 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 TPEX cell frequencies have recently been linked to increased patient survival. We believe the recent discovery of TPEX 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 TPEX cells and suggest that targeting these cells may be key for successful immunotherapy.
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The authors thank the members of the Kallies and Zehn laboratories, in particular S. Gabriel, A. Vasanthakumar and P. Gubser for discussions. A.K. is a fellow of the Australian National Health and Medical Research Council. D.T.U. is a special fellow of The Leukemia and Lymphoma Society.
Nature Reviews Immunology thanks N. Restifo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
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The Nobel Prize in Physiology or Medicine 2018: https://www.nobelprize.org/prizes/medicine/2018/summary/
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Kallies, A., Zehn, D. & Utzschneider, D.T. Precursor exhausted T cells: key to successful immunotherapy?. Nat Rev Immunol 20, 128–136 (2020). https://doi.org/10.1038/s41577-019-0223-7
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