Abstract
CD8+ T cells specific for cancer cells are detected within tumours. However, despite their presence, tumours progress. The clinical success of immune checkpoint blockade and adoptive T cell therapy demonstrates the potential of CD8+ T cells to mediate antitumour responses; however, most patients with cancer fail to achieve long-term responses to immunotherapy. Here we review CD8+ T cell differentiation to dysfunctional states during tumorigenesis. We highlight similarities and differences between T cell dysfunction and other hyporesponsive T cell states and discuss the spatio-temporal factors contributing to T cell state heterogeneity in tumours. An important challenge is predicting which patients will respond to immunotherapeutic interventions and understanding which T cell subsets mediate the clinical response. We explore our current understanding of what determines T cell responsiveness and resistance to immunotherapy and point out the outstanding research questions.
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Acknowledgements
The authors are grateful for support from the V Foundation Scholar Award (M.P.), Vanderbilt Digestive Disease Research Center Young Investigator and Pilot Award (P30DK058404) (M.P.), the Vanderbilt-Ingram Cancer Center Breast Cancer SPORE Career Enhancement Program (P50CA098131) (M.P.), NIH NCI grants DP2CA225212 (A.S.) and U54CA209975, the Lloyd Old Star Awards Program from the Cancer Research Institute (A.S.), the Pershing Square Award (A.S.), and the Josie Robertson Young Investigator Award (A.S.).
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Glossary
- Immune checkpoint blockade
-
(ICB). Therapy for cancer using specific antibodies that block interactions between inhibitory ‘checkpoint’ receptors on immune cells and their ligands on cancer and stromal cells.
- Central tolerance
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A process occurring during thymic T cell development in which thymocytes bearing rearranged T cell receptors with too high affinity for self-antigen–MHC complexes are eliminated (negative selection).
- Peripheral tolerance
-
Process by which self-reactive T cells that escaped central tolerance and entered the periphery are inactivated by induction of apoptosis (peripheral deletion), suppression by CD4+ regulatory T cells or induction of cell-intrinsic hyporesponsive programmes (tolerance).
- Cold tumours
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Non-T-cell-inflamed tumours as opposed to hot tumours, which are T cell-inflamed tumours that have high levels of inflammatory cytokines and T cell infiltration and are associated with a better response to immune checkpoint blockade.
- Tertiary lymphoid structures
-
Organized immune cell aggregates within parenchymal tissues similar to secondary follicles in lymph nodes, comprising a T cell zone of mainly helper and follicular helper CD4+ T cells and mature dendritic cells, as well as a follicular zone with B cells and follicular dendritic cells.
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Philip, M., Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat Rev Immunol 22, 209–223 (2022). https://doi.org/10.1038/s41577-021-00574-3
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DOI: https://doi.org/10.1038/s41577-021-00574-3
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