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.

Persistent donor derived Vδ4 T cell clones may improve survival for recurrent T cell acute lymphoblastic leukemia after HSCT and DLI

“…These results may support that the donor derived Vδ4 T cell clone we identified here may be specific to any T-ALL antigen and work efficiently for lysing T-ALL blasts. For confirming the function of Vδ4 T cells, TCR γδ gene could be cloned from this Vδ4 T cells and transferred to healthy T cells to detect the specific cytotoxicity [28, 29]. If the anti-leukemia effect could be confirmed, such clonally expanded Vδ4 T cells in this case may be considered as specific DLI to avoid GvHD development.…”

Comparison of two cytoreductive regimens for αβ‐T‐cell‐depleted haploidentical HSCT in pediatric malignancies: Improved engraftment and outcome with TBI‐based regimen

“…The T‐cell receptor (TCR) is composed of several chains, and its specificity is determined by the alpha and beta chains (αβ‐TCR) or in a subset of T cells by the gamma and delta chains (γδ‐TCR). Contrary to αβ‐TCR, which recognizes short peptides presented by HLA molecules, γδ‐TCR responds to a distinct set of antigens, such as bacterial phospho‐antigens and lipids, independent of antigen processing and presentation, and hence are considered non‐allo‐reactive cells. γδ‐T cells have demonstrated antitumor properties against a variety of tumors in preclinical studies and early clinical trials .…”

Human Peripheral Blood Gamma Delta T Cells: Report on a Series of Healthy Caucasian Portuguese Adults and Comprehensive Review of the Literature

“…Vδ2 Tc respond mainly to intracellular bacteria and solid tumors, while Vδ1 Tc, resident mainly in tissues, is used mostly in the defense against viruses and malignancies, although this dichotomy is not absolute. In addition, γδ T-cells are being explored in cell-based immunotherapy [20][21][22].In parallel to the low frequency of γδ Tc, lymphoproliferative disorders (LPD) of γδ Tc are rare disease conditions. These comprise γδ Tc large granular lymphocyte (LGL) proliferations, including γδ Tc LGL leukemia, defined as clonal expansions of cytotoxic γδ Tc, which have an indolent clinical course and often coexist with cytopenias and other pathologies [23,24], and hepatosplenic and other γδ Tc lymphomas, which usually have an aggressive clinical course, poor response to chemotherapy and short survival [25][26][27][28].Gamma delta Tc expressing Vγ9Vδ2 are known to identify microbe-derived (e.g., (E)-4-hydroxy-3methyl-but-2-enyl pyrophosphate, HMB-PP) and host-derived (e.g., isopentenyl pyrophosphate, IPP) phosphorylated metabolites ("phosphoantigens") originating from the isoprenoid metabolic mevalonate and non-mevalonate pathways, through association with butyrophilin 3A1 (B3A1) [29,30].…”

“…Vδ2 Tc respond mainly to intracellular bacteria and solid tumors, while Vδ1 Tc, resident mainly in tissues, is used mostly in the defense against viruses and malignancies, although this dichotomy is not absolute. In addition, γδ T-cells are being explored in cell-based immunotherapy [20][21][22].…”