Review Article | Published:

Targeting tumours with genetically enhanced T lymphocytes

Abstract

The genetic modification of T lymphocytes is an important approach to investigating normal T-cell biology and to increasing antitumour immunity. A number of genetic strategies aim to increase the recognition of tumour antigens, enhance antitumour activities and prevent T-cell malfunction. T cells can also be engineered to increase safety, as well as to express markers that can be tracked by non-invasive imaging technologies. Genetically modified T cells are therefore proving to be of great value for basic immunology and experimental immunotherapy.

Key Points

  • The genetic modification of T lymphocytes is the basis for novel approaches to study tumour immunity.

  • Antigen specificity can be redirected by the transduction of physiological and chimeric antigen receptors into T cells.

  • T-cell proliferation and function can be increased by genetically manipulating cells to express modified co-stimulatory receptors.

  • T cells can be genetically protected from immunosuppressive factors such as transforming growth factor-β.

  • T cells can also be genetically modified to include regulatable suicide mechanisms, thereby ensuring the safety of adoptive-cell therapy.

  • Expressing constitutive or inducible markers in T cells allows the tracking of cell migration and activation using non-invasive imaging technologies.

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Acknowledgements

Our work is primarily supported by National Institutes of Health grants and the Goodwin ETC fund. We thank K. Hurdle and E. Ciccaroni for excellent assistance with the preparation of the manuscript and the figures.

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Correspondence to Michel Sadelain.

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Glossary

CYTOTOXIC T LYMPHOCYTES

(CTLs). T lymphocytes that exert a cytolytic function following engagement of their T-cell antigen receptor on target cells. CTLs express the co-receptor CD8 and recognize antigenic peptides (or CTL epitopes) that are presented by HLA class I molecules.

ANERGY

A state of unresponsiveness to antigen that can be induced when the T-cell receptor binds antigen in the absence of co-stimulation.

HYBRIDOMA

A cell line that is created by the fusion of a lymphocyte tumour cell to an antigen-specific T-cell clone. This fusion results in a T-cell line that maintains the specificity of the T-cell clone as well as the immortalized phenotype of the tumour cell.

PRIMARY T CELLS, T-CELL LINES AND CLONES

Primary T cells are cells that have been freshly harvested from the donor and have not undergone transformation or extensive culture. Hybridomas, leukaemias and lymphomas are transformed cells that might not faithfully reflect or recapitulate the activation requirements or differentiation of primary T cells. T-cell lines are obtained by periodic restimulation of cultured primary T cells. T-cell clones are the progeny of a single primary T cell.

HUMAN LEUKOCYTE ANTIGENS

(HLAs). Cell-surface molecules that are encoded by the major histocompatibility complex. These molecules present antigenic peptides to T cells via their T-cell antigen receptor. HLA class I molecules present antigen to CD8+ T lymphocytes, and HLA class II molecules present antigen to CD4+ lymphocytes.

HELPER T LYMPHOCYTES

T lymphocytes that exert regulatory and helper functions for B cells, cytotoxic T lymphocytes and other immune effector cells. Helper T cells express the co-receptor CD4, which recognizes antigenic peptides (or helper epitopes) that are presented by HLA class II molecules.

MEMORY LYMPHOCYTES

Long-lived clonal T cells that develop following a primary immune response. This T-cell population mediates the secondary T-cell response that is seen following late re-exposure to the cognate antigen.

IMMUNOLOGICAL SYNAPSE

A term that is used to describe the supra-molecular structure that is established between a T cell and an antigen-presenting cell (APC) bearing the HLA-peptide complex recognized by the T-cell antigen receptor (TCR). At the centre of the synapse, adhesion is mediated through binding of the TCR to the APC's HLA-peptide complex. Peripherally, this complex is stabilized through additional interactions — for example, between LFA1 and ICAM1.

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Further reading

Figure 1: Structure of physiological antigen receptors.
Figure 2: Examples of chimeric antigen receptors.
Figure 3: Co-stimulation of tumour-reactive T cells in vivo.