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γδ T cells in cancer

Nature Reviews Immunology volume 15, pages 683–691 (2015)Cite this article

Subjects

Key Points

  • γδ T cells are endowed with unique specificities, high clonal frequencies and a pre-activated differentiation status that allow rapid and non-redundant responses to tumours.

  • Mice lacking γδ T cells have been shown to be more susceptible (than wild-type controls) to a variety of inducible tumours, but recent studies on distinct cancer models scored reduced tumour growth in γδ T cell-deficient animals, implying unanticipated protumour roles.

  • A dichotomy has emerged from mouse tumour models in which interferon-γ (IFNγ)-producing γδ T cells are potent antitumour effectors, whereas interleukin-17 (IL-17)-secreting γδ T cells can promote tumour cell growth, often by recruitment of pro-inflammatory or immunosuppressive myeloid cells.

  • IL-17 is readily produced (from embryonic stages) by mouse γδ T cells, but it is rarely observed in human γδ T cells except in highly inflammatory conditions, which seem to include some cancer types. Further investigation is required to substantiate this conclusion.

  • γδ T cells can recognize tumour cells through their T cell receptor (TCR) or natural killer cell receptors (NKRs), most notably NKG2D that binds to ligands often induced or overexpressed upon transformation. The identity of the tumour antigens recognized by γδ TCRs remains largely unknown for both mouse and human γδ T cells.

  • Human γδ T cells include the Vγ9Vδ2 subset that predominates in the blood and the Vδ1 subset that is highly enriched within healthy and malignant tissues. While all clinical trials have thus far concentrated on Vγ9Vδ2+ T cells, enhanced cytotoxic performance and resistance to both T cell exhaustion and activation-induced cell death may render Vδ1+ T cells particularly suitable for adoptive cell therapy of cancer.

Abstract

With the promise of T cell-based therapy for cancer finally becoming reality, this Review focuses on the less-studied γδ T cell lineage and its diverse responses to tumours. γδ T cells have well-established protective roles in cancer, largely on the basis of their potent cytotoxicity and interferon-γ production. Besides this, recent studies have revealed a series of tumour-promoting functions that are linked to interleukin-17-producing γδ T cells. Here, we integrate the current knowledge from both human and mouse studies to highlight the potential of γδ T cell modulation to improve cancer immunotherapy.

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Figure 1: Antitumour versus protumour roles of mouse γδ T cells.
Figure 2: Receptor–ligand interactions mediating tumour cell recognition by human γδ T cells.

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Acknowledgements

The authors thank A. Hayday for critical reading of the manuscript and D. Pennington, M. Rei, T. Lança, D. Correia, J. Ribot, S. Chiplunkar and F. Dieli for insightful discussions on this topic. Their work was funded by the European Research Council (StG_260352 to B.S.-S.), and the Investigator FCT (to K.S.) and Welcome II (to H.N.) programmes of Fundação para a Ciência e Tecnologia.

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  1. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, Lisboa, 1649-028, Portugal

    Bruno Silva-Santos, Karine Serre & Håkan Norell

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  1. Bruno Silva-Santos
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  2. Karine Serre
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Correspondence to Bruno Silva-Santos or Karine Serre.

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B.S.-S. is co.founder and shareholder of Lymphact S.A.

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Glossary

Somatic recombination

The somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both T cell and B cell receptors; it is also known as V(D)J recombination.

NKG2D

A C-type lectin-like receptor that binds to multiple stress or transformation-inducible ligands of the non-classical MHC (class Ib) family H60, murine UL16-binding protein-like transcript 1 (MULT1) and members of the retinoic acid early inducible 1 (RAE1) proteins in mice; and MHC class I-related chain A or B (MICA and MICB) and UL16-binding proteins (ULBP1–ULBP6) in humans.

Myeloid-derived suppressor cells

(MDSCs). A group of immature CD11b+GR1+ cells (which include precursors of macrophages, granulocytes, dendritic cells and myeloid cells) that are produced in response to various tumour-derived cytokines. These cells have been shown to induce tolerance in tumour-associated CD8+ T cells.

T cell exhaustion

The impaired ability of effector T cells to carry out their functions, such as cytotoxicity and cytokine secretion, owing to chronic stimulation by antigens. It is typified by increased surface expression of programmed cell death 1.

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Silva-Santos, B., Serre, K. & Norell, H. γδ T cells in cancer. Nat Rev Immunol 15, 683–691 (2015). https://doi.org/10.1038/nri3904

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