Paths to stemness: building the ultimate antitumour T cell

Key Points

  • T lymphocytes transition through progressive stages of differentiation that are characterized by a stepwise loss of functional and therapeutic potential.

  • Subsets of mature T cells exhibit the stem cell-like attributes of self-renewal, multipotency and the ability to undergo asymmetric division.

  • Evolutionarily conserved pathways regulating stemness are active in T cells, including T memory stem cells, T helper 17 cells and interleukin-17 (IL-17)-producing CD8+ T cells.

  • Pharmacological and genetic induction of stem cell pathways can be used to generate tumour-specific T cells with stem cell-like properties.

  • Reprogramming terminally differentiated tumour-reactive T cells to display naive or stem cell-like functionalities might be obtained through the expression of transcription factors or microRNAs that are associated with naive or T memory stem cells.

  • Stem cell-like T cells possess enhanced capacities to engraft, persist and mediate prolonged immune attack against tumour masses that are sustained by long-lived cancer stem cells.

Abstract

Stem cells are defined by the ability to self-renew and to generate differentiated progeny, qualities that are maintained by evolutionarily conserved pathways that can lead to cancer when deregulated. There is now evidence that these stem cell-like attributes and signalling pathways are also shared among subsets of mature memory T lymphocytes. We discuss how using stem cell-like T cells can overcome the limitations of current adoptive T cell therapies, including inefficient T cell engraftment, persistence and ability to mediate prolonged immune attack. Conferring stemness to antitumour T cells might unleash the full potential of cellular therapies.

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Figure 1: A model of progressive T cell differentiation.
Figure 2: Signalling pathways regulating self-renewal and differentiation shared between stem cells and T lymphocytes.
Figure 3: Fighting fire with fire.
Figure 4: Strategies that might be used to preserve or to confer stemness to T cells.

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Acknowledgements

This work was supported by the National Institutes of Health, Center for Regenerative Medicine (NIH-CRM) and by the Center for Cancer Research (CCR) by the US National Cancer Institute (Bethesda, Maryland). The authors would like to thank M. Rao for helpful discussions about regenerative medicine. M. Bachinski copyedited the manuscript during construction. J. Crompton, R. Roychoudhuri, P. Muranski, D. Palmer, Y. Ji, M. Sukumar, J. Pan, A. Leonardi, Z. Franco, Z. Yu and D. Clever provided a lively sounding board for concepts presented here. J. C. Yang, U. S. Kammula, R. A. Morgan, S. A. Feldman, P. F. Robbins, R. M. Sherry, M. Parkhurst, M. Hughes and G. Phan made many valuable suggestions regarding the clinical translation of the work described. The authors would especially like to thank our longtime stalwart ally in all of these efforts S. A. Rosenberg.

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Glossary

Self-renewal

A biological process by which a cell gives rise to one or two daughter cells that have a developmental potential that is indistinguishable from that of the mother cell.

Multipotency

The potential for a cell to give rise to progeny with the capacity to form multiple, but not all possible, lineages.

Tumour-infiltrating lymphocytes

(TILs). The heterogeneous population of T cells found in a tumour bed. These cells are characterized by a diversity of phenotypes, antigen specificities, avidities and functional characteristics. They can be activated and expanded ex vivo and re-infused into a tumour-bearing host to mediate tumour regression.

Mass cytometry

Also known as cytometry by time-of-flight (CyTOF). A platform that couples flow cytometry with mass spectrometry. This technique enables the simultaneous evaluation of at least 45 simultaneous phenotypic and functional parameters on a single cell without the use of fluorescent agents or interference from spectral overlap.

Senescence

A biological process by which cells undergo growth arrest after extensive replication.

Homeostatic proliferation

A process of activation and proliferation of leukocytes in a lymphopaenic environment. T cell homeostatic proliferation is driven by T cell receptor interactions with self-peptide–MHC complexes and responsiveness to homeostatic cytokines such as interleukin-7 (IL-7), IL-15 and possibly IL-21.

TCR excision circles

(TRECs). Circular, stable extra-chromosomal DNA fragments that are generated during recombination of variable (V), diversity (D) and joining regions (J) of the T cell receptor. TRECs do not replicate with cellular proliferation and are thus diluted with every cell division, allowing the assessment of the replicative history of a T cell.

Asymmetric cell division

A conserved mechanism by which a cell divides into daughter cells of unequal size and cytoplasmic content, thus conferring differential developmental fates to progeny cells.

Telomere

The segment at the end of chromosomal arms consisting of a series of repeated DNA sequences (TTAGGG in all vertebrates) that regulates chromosomal replication at each cell division.

Stem cell niche

A specialized microenvironment containing stem cells that supports their maintenance and regulates their function.

Common γ-chain

C). A signalling subunit common to the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21.

Exhaustion

A state of T cell dysfunction arising during reiterative antigen stimulations such as chronic infections and cancer. It is defined by poor effector function and proliferative response to antigenic stimuli, expression of inhibitory receptors and a transcriptional state that is distinct from that of functional effector or memory T cells.

Autosomal-dominant hyper-IgE syndrome

(AD-HIES). Also known as Job's syndrome. A rare primary immunodeficiency characterized by recurrent skin abscesses, cyst-forming pneumonias and extreme increases of serum IgE levels. Most AD-HIES cases are caused by dominant-negative mutations in STAT3.

Epigenetic modifications

Heritable molecular alterations of the genome that do not involve changes to the nucleotide sequence that regulates gene or microRNA expression. They include DNA methylation, histone modifications and nucleosome positioning.

Induced pluripotent stem (iPS) cells

Pluripotent stem cells artificially derived from non-pluripotent cells, such as an adult somatic cell by forced expression of specific genes or microRNAs.

Suicide genes

Genes capable of selectively eliminating the cells into which they have been transduced following the administration of a drug.

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Gattinoni, L., Klebanoff, C. & Restifo, N. Paths to stemness: building the ultimate antitumour T cell. Nat Rev Cancer 12, 671–684 (2012). https://doi.org/10.1038/nrc3322

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