The promise of γδ T cells and the γδ T cell receptor for cancer immunotherapy

Abstract

γδ T cells form an important part of adaptive immune responses against infections and malignant transformation. The molecular targets of human γδ T cell receptors (TCRs) remain largely unknown, but recent studies have confirmed the recognition of phosphorylated prenyl metabolites, lipids in complex with CD1 molecules and markers of cellular stress. All of these molecules are upregulated on various cancer types, highlighting the potential importance of the γδ T cell compartment in cancer immunosurveillance and paving the way for the use of γδ TCRs in cancer therapy. Ligand recognition by the γδ TCR often requires accessory/co-stimulatory stress molecules on both T cells and target cells; this cellular stress context therefore provides a failsafe against harmful self-reactivity. Unlike αβ T cells, γδ T cells recognise their targets irrespective of HLA haplotype and therefore offer exciting possibilities for off-the-shelf, pan-population cancer immunotherapies. Here, we present a review of known ligands of human γδ T cells and discuss the promise of harnessing these cells for cancer treatment.

Figure 1

V(D)J recombination at the tcrg (upper panel) and tcra/tcrd (lower panel) locus. Only the functional gene segments are shown. The TCR-γ chain is produced using only a single V-J recombination, with P/N additions occurring at the V-J junction. The TCR-δ chain is produced using V-D-J recombinations that can involve either 2 or 3 D segments, leading to the creation of up to 4 N diversity regions. For the clarity of the figure, only the gene segments that can be used in TCR-δ chain production are presented (lower panel). The organisation of loci tcrg and tcra/tcrd was adapted from IMGT database.

Figure 2

9C2 γδ TCR protein structure (left panel) and γ and δ chain mRNA architecture (right panel). The CDR loops are colour-coded. PDB ID: 4LHU.

Figure 3

(a) Schematic representation of the phosphoantigen presentation pathways by human cells showing phosphoantigen (IPP) binding in the extracellular pocket of BTN3A1 (b) and phosphoantigen (cHDMAPP) binding in the intracellular domain (B30.2) of BTN3A1 (C). PDB IDs: 4JKW (B) and 4N7U (C).

Figure 4

Complex formation between TCR and CD1 ligands. CDR loops are colour coded as in Figure 2: CDR1δ-red, CDR2δ-green, CDR3δ-blue, CDR1γ-yellow, CDR2γ-cyan and CDR3γ-orange. The blue loop in panel C is CDR3δ/α. PDB IDs: 4MNG (A), 4LHU (B), 4WO4 (C).

Figure 5

Recognition of γδ TCR ligands requires a cell stress context. (a) Recognition of EPCR requires co-stimulatory ligands on the surface of the target cells, and accessory molecules on the surface of the T cell. (b) Both hMSH2 and MIC A become upregulated and ectopically expressed in response to cell stress stimuli and are dually recognised by NKG2D and TCR. The sequential model of recognition implies that the initial contact provided by a transient high-affinity NKG2D–ligand interaction (1) is followed by formation of a stable low affinity TCR-ligand complex (2).

Figure 6

Genetic modification of γδ T cells for adoptive therapy approaches to cancer. (a) γδ T cells can be redirected to kill cancer cells using a chimeric antigen receptor (CAR) made from an antibody that targets a tumour-specific molecule at the cancer cell surface. (b) αβ T cells can be redirected to kill cancer cells by transducing them with a cancer-specific αβ TCR. Such αβ TCR gene transfer could result in the expression of up to four different αβ TCRs at the T cell surface: (i) the endogenous TCR; (ii) the transduced TCR; (iii) a hybrid TCR consisting of the endogenous TCRα chain paired with the transduced TCRβ chain; and (iv) endogenous TCRβ chain paired with the transduced TCRα chain. Neither hybrid will have undergone the rigours of thymic selection and therefore these TCRs have the potential of being autoreactive. (c) Transduction of γδ T cells with an αβ TCR provides a means of circumventing the potential mispairing problem seen in b.