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γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer

Nature Reviews Cancer volume 19, pages 392–404 (2019)Cite this article

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Abstract

The potential of cancer immunotherapy relies on the mobilization of immune cells capable of producing antitumour cytokines and effectively killing tumour cells. These are major attributes of γδ T cells, a lymphoid lineage that is often underestimated despite its major role in tumour immune surveillance, which has been established in a variety of preclinical cancer models. This situation notwithstanding, in particular instances the tumour microenvironment seemingly mobilizes γδ T cells with immunosuppressive or tumour-promoting functions, thus emphasizing the importance of regulating γδ T cell responses in order to realize their translation into effective cancer immunotherapies. In this Review we outline both seminal work and recent advances in our understanding of how γδ T cells participate in tumour immunity and how their functions are regulated in experimental models of cancer. We also discuss the current strategies aimed at maximizing the therapeutic potential of human γδ T cells, on the eve of their exploration in cancer clinical trials that may position them as key players in cancer immunotherapy.

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Fig. 1: Timeline of developments in the research of γδ T cell function in cancer and their exploitation for immunotherapy.
Fig. 2: Antitumour γδ T cell functions and their regulation.
Fig. 3: Pro-tumour γδ T cell functions and their regulation.
Fig. 4: Current strategies for therapeutic manipulation of human γδ T cells.

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Acknowledgements

We thank D. Correia, A. Simões, H. Norell and K. Serre (iMM JLA) for insightful discussions on this topic. We acknowledge funding from the European Research Council (CoG_646701 to B.S.-S.), Cancer Research UK Glasgow Centre (A25142 to S.B.C.), Breast Cancer Now (2018JulPR1101 to S.B.C.), Wellcome Trust (208990/Z/17/Z to S.B.C.), Tenovus Scotland (Project S17-17 to S.B.C.) and Fundação para a Ciência e a Tecnologia / Ministério da Ciência, Tecnologia e Ensino Superior through Fundos do Orçamento de Estado (refs. UID/BIM/50005/2019 and PD/BD/114099/2015).

Reviewer information

Nature Reviews Cancer thanks W. Havran, B. Willcox and F. Dieli for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Bruno Silva-Santos & Sofia Mensurado

  2. Institute of Cancer Sciences, University of Glasgow and Cancer Research UK Beatson Institute, Glasgow, UK

    Seth B. Coffelt

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  1. Bruno Silva-Santos
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  2. Sofia Mensurado
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  3. Seth B. Coffelt
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Contributions

B.S.-S., S.M. and S.B.C. researched the data for the article and contributed equally to the writing as well as to the review and/or editing of the manuscript before submission.

Corresponding authors

Correspondence to Bruno Silva-Santos or Seth B. Coffelt.

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Competing interests

B.S.-S. is a co-founder and shareholder of Lymphact, the company that developed DOT cells, which was acquired in 2018 by GammaDelta Therapeutics (London, UK). S.M. and S.B.C. declare no competing interests.

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Glossary

Triplebodies

Immunoligands consisting of three tandem single-chain variable fragments with three distinct specificities.

Aminobisphosphonate

A drug type that derives from bisphosphonates and is commonly used in bone-related disorders to avoid excessive bone resorption.

Immunoglobulin class switching

Mechanism by which B cells change the isotype of immunoglobulin produced, altering its effector function.

Germinal centre

A site within the spleen and lymph nodes where B cells proliferate, differentiate and perform immunoglobulin class switching.

V(D)J recombination

Also known as 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.

Angiogenic switch

Time point during tumour progression when the pro-angiogenic factors outcompete the antiangiogenic ones, leading to transition between a dormant avascularized hyperplasia and an outgrowing vascularized tumour.

Thymocytes

Haematopoietic progenitor cells present in the thymus gland.

Oxygen tension

Partial pressure of oxygen molecules dissolved in a liquid (such as blood plasma).

Mevalonate pathway

Also known as the isoprenoid pathway. An essential metabolic pathway that gives rise to two five-carbon building blocks, called isopentenyl pyrophosphate and dimethylallyl purophosphate, that are converted into isoprenoids. Metabolites of this pathway accumulate in metabolically distressed cells.

Nanobody

An antibody with a single monomeric domain.

Stereotaxic administration

Delivery of a compound into the brain using an external, three-dimensional frame of reference, usually based on the Cartesian coordinate system.

Haploidentical stem cell transplantation

Treatment of blood disorders involving the replacement of the patient’s haematopoietic cells by healthy partially (50%) human leukocyte antigen-matched haematopoietic progenitors.

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Silva-Santos, B., Mensurado, S. & Coffelt, S.B. γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nat Rev Cancer 19, 392–404 (2019). https://doi.org/10.1038/s41568-019-0153-5

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