Translating gammadelta (γδ) T cells and their receptors into cancer cell therapies

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Clinical responses to checkpoint inhibitors used for cancer immunotherapy seemingly require the presence of αβT cells that recognize tumour neoantigens, and are therefore primarily restricted to tumours with high mutational load. Approaches that could address this limitation by engineering αβT cells, such as chimeric antigen receptor T (CAR T) cells, are being investigated intensively, but these approaches have other issues, such as a scarcity of appropriate targets for CAR T cells in solid tumours. Consequently, there is renewed interest among translational researchers and commercial partners in the therapeutic use of γδT cells and their receptors. Overall, γδT cells display potent cytotoxicity, which usually does not depend on tumour-associated (neo)antigens, towards a large array of haematological and solid tumours, while preserving normal tissues. However, the precise mechanisms of tumour-specific γδT cells, as well as the mechanisms for self-recognition, remain poorly understood. In this Review, we discuss the challenges and opportunities for the clinical implementation of cancer immunotherapies based on γδT cells and their receptors.

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Fig. 1: Molecules involved in mediating the recognition of healthy and cancer cells through a γδTCR.
Fig. 2: γδTCR and co-receptor diversity.
Fig. 3: Potential causes for failures of clinical trials utilizing natural γδT cells.
Fig. 4: Selected therapeutic concepts.


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The authors appreciate the support of D. Beringer for the illustrations provided here of chemicals and crystal structures. Funding for this study was provided by grants ZonMW 43400003, VIDI-ZonMW 917.11.337, KWF UU 2013-6426, UU 2014-6790, UU 2015-7601, UU2018-11979 and GADETA to J.K.; UU2017-11393 to Z.S. and J.K.; European Research Council grant CoG_646701 to B.S.S.; and DFG grant FOR 2799-PR727/11-1 to I.P.; as well as by Ligue Contre le Cancer (Equipe labellisée 2017) and SIRIC BRIO grants to J.D.M.

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The authors contributed equally to all aspects of the article.

Correspondence to Jurgen Kuball.

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Competing interests

J.D.M. is scientific adviser of American Gene Technologies; B.S.S. is a cofounder of Lymphact SA, a shareholder and scientific adviser of GammaDelta Therapeutics, and an inventor on patents dealing with DOT cells. J.K. is cofounder, shareholder and scientific adviser of GADETA and inventor on multiple patents dealing with gdTCR and their ligands, as well as with isolation techniques for engineered immune cells. Z.S. is an inventor of patents dealing with gdTCR and their ligands. I.P. declares no competing interests.

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Vγ9Vδ2 T cells

The main circulating human γδT cells, in which their γδ T cell receptor (TCR) heterodimer is built by a TCRγ chain that uses a Vγ9 segment and a TCRδ chain using the variable (V) segment Vδ2. Vγ9Vδ2 T cells display a relatively limited diversity of their individually rearranged TCR sequences, and are therefore regarded as semi-invariant.

Vδ1+ T cells

A subset of human γδT cells in which their T cell receptor (TCR) uses a Vδ1 segment for its TCRδ chain. TCRδ sequences of Vδ1+ T cells are more diverse than those of Vγ9Vδ2 T cells, and the repertoire of Vδ1+ T cells is further expanded by pairing with different TCRγ chains (using Vγ2, 3,4,5,8, and non-invariant Vγ9 segments). Vδ1+ T cells have been reported to recognize a wide range of cancer cells.

non-Vγ9Vδ2 γδT cells

All human γδT cells except Vγ9Vδ2 γδT cells, including TCRδ chain 1 or 3 to 8, and any Vγ chains (Vγ2, 3, 4, 5, 8, 9).


Intracellular metabolites of the mevalonate pathway, such as isopentenyl pyrophosphate (IPP), or metabolites derived from the mevalonate-independent 1-deoxy-d-xylulose 5-phosphate (DOXP) pathway in bacteria or parasites. (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is produced by several bacteria and parasites and is the most powerful stimulant for Vγ9Vδ2 T cells. Also, synthetic phosphoantigens have been reported, such as bromohydrin pyrophosphate (BrHPP) and 2-methyl-3-butenyl-1-pyrophosphate (2M3B1PP).


Metabolites such as pamidronate or zoledronate that partially block the natural mevalonate pathway after the production of isopentenyl pyrophosphate (IPP), through inhibiting farnesyl pyrophosphate synthase, and thereby increase IPP levels. Aminobisphosphonates have been used in daily clinical practice for decades — for example, in patients with multiple myeloma — to stabilize bone formation, mainly because of their inhibitory effect on osteoclasts.

Natural killer T cells

(NKT cells). Immune cells that share properties of αβT cells and NK cells. The αβTCR of NKT cells expresses the invariant TCR Vα24 chain, characterized by their usage of the Jα18 segment in humans. Most NKT cells recognize through their αβTCR lipids expressed within the context of CD1c or CD1d.

Cytotoxic type 1 phenotype

Ability in αβ and γδ T cells to mediate the killing of target cells through the secretion of granzymes and perforin. Such T cells usually also produce IFNγ and TNF.


State of an immune cell, which correlates with loss of function and can also result in deletion, and thus the complete loss of defined γδT cells.

Regulatory γδT cells

(Treg cells). A subpopulation of T cells that modulate the immune system. Until recently regulatory cells have been attributed solely to αβT cells, and they are characterized by the expression of CD4, CD25 and FOXP3, with a subset also producing IL-17. Now it has also been proposed that γδT cells have regulatory properties and that regulatory γδT cells secrete IL-17 and mediate tolerance against cancer cells.

Tolerogeneic profile

Immune cells secreting cytokines that induce tolerance, such as IL-10 and IL-17, or enhance the expression of inhibitory checkpoint molecules in their microenvironment.


Monoclonal antibody that activates immune cells by targeting CTLA4.

Cytokine release syndrome

Mild to life-threatening syndrome caused by a rapid release of cytokines after adoptive transfer of CAR T cells or other types of immune therapy.

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