Abstract
T cells can acquire a broad spectrum of differentiation states following activation. At the extreme ends of this continuum are short-lived cells equipped with effector machinery and more quiescent, long-lived cells with heightened proliferative potential and stem cell-like developmental plasticity. The latter encompass stem-like exhausted T cells and memory T cells, both of which have recently emerged as key determinants of cancer immunity and response to immunotherapy. Here, we discuss key similarities and differences in the regulation and function of stem-like exhausted CD8+ T cells and memory CD8+ T cells, and consider their context-specific contributions to protective immunity in diverse outcomes of cancer, including tumour escape, long-term control and eradication. Finally, we emphasize how recent advances in the understanding of the molecular regulation of stem-like exhausted T cells and memory T cells are being explored for clinical benefit in cancer immunotherapies such as checkpoint inhibition, adoptive cell therapy and vaccination.
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Acknowledgements
T.G. is supported by an Investigator Fellowship from the National Health and Medical Research Council Australia (APP1194482). S.L.P. is supported by a Cancer Research Institute Irvington Postdoctoral Fellowship (CRI3383). I.A.P. is supported by Victorian Cancer Agency Mid-Career Fellowship (21019).
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T.G. and I.A.P. conceptualized the article and figures. All authors contributed to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.
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T.G. is a scientific advisory board member of oNKo Innate Pty. Ltd and has received research funding from Merck Healthcare KGaA. I.A.P. receives research funding from AstraZeneca and Bristol-Myers Squibb. S.L.P. declares no competing interests.
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Glossary
- Adaptive immune cells
-
Cells of the acquired arm of the immune system that mounts an antigen-specific response; these include T cells and B cells.
- Chimeric antigen receptor
-
(CAR). A genetically engineered T cell receptor (TCR) molecule combining major histocompatibility complex (MHC)-independent specificity for cancer antigens with strong T cell activation intracellular signalling domains.
- Epitope spreading
-
A broadening of the spectrum of antigens that immune cells target in a cancer, typically triggered by tumour destruction.
- Innate immune cells
-
Cells of the innate arm of the immune system that generates rapid responses upon infection, typically triggered by recognition of conserved pathogen-associated or danger-associated molecular structures; these include natural killer cells and other innate lymphocytes, dendritic cells (DCs), monocytes, macrophages, granulocytes and mast cells.
- Neoantigens
-
New proteins that arise from gene mutations in cancer cells and are recognized by T cells as foreign.
- Perivascular niches
-
Aggregations of immune cells such as T cells and dendritic cells (DCs) in close proximity to tumour blood vessels.
- Pseudotime analysis
-
An analysis of the differentiation trajectory of T cells based on transcriptional data.
- Terminal exhaustion
-
A T cell differentiation state driven by chronic antigen stimulation that is characterized by diminished effector functions, poor proliferative capacity and compromised cell survival.
- Tertiary lymphoid structures
-
Aggregation of ectopic lymphoid tissues consisting of T cells, B cells and dendritic cells (DCs) that form in chronically inflamed tissues such as tumours.
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Gebhardt, T., Park, S.L. & Parish, I.A. Stem-like exhausted and memory CD8+ T cells in cancer. Nat Rev Cancer 23, 780–798 (2023). https://doi.org/10.1038/s41568-023-00615-0
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DOI: https://doi.org/10.1038/s41568-023-00615-0
