Effective γδ T-cell clinical therapies: current limitations and future perspectives for cancer immunotherapy

Abstract

γδ T cells are a unique subset of T lymphocytes, exhibiting features of both innate and adaptive immune cells and are involved with cancer immunosurveillance. They present an attractive alternative to conventional T cell-based immunotherapy due, in large part, to their lack of major histocompatibility (MHC) restriction and ability to secrete high levels of cytokines with well-known anti-tumour functions. To date, clinical trials using γδ T cell-based immunotherapy for a range of haematological and solid cancers have yielded limited success compared with in vitro studies. This inability to translate the efficacy of γδ T-cell therapies from preclinical to clinical trials is attributed to a combination of several factors, e.g. γδ T-cell agonists that are commonly used to stimulate populations of these cells have limited cellular uptake yet rely on intracellular mechanisms; administered γδ T cells display low levels of tumour-infiltration; and there is a gap in the understanding of γδ T-cell inhibitory receptors. This review explores the discrepancy between γδ T-cell clinical and preclinical performance and offers viable avenues to overcome these obstacles. Using more direct γδ T-cell agonists, encapsulating these agonists into lipid nanocarriers to improve their pharmacokinetic and pharmacodynamic profiles and the use of combination therapies to overcome checkpoint inhibition and T-cell exhaustion are ways to bridge the gap between preclinical and clinical success. Given the ability to overcome these limitations, the development of a more targeted γδ T-cell agonist-checkpoint blockade combination therapy has the potential for success in clinical trials which has to date remained elusive.

Keywords: bisphosphonates; combination therapy; immunotherapy; lipid nanocarriers; nanomedicine; γδ T cells.

Figure 1

γδ T‐cell‐mediated cytotoxicity against tumour or infected cells. Inset shows HMBPP binding to the binding pocket of the intracellular B30.2 domain of BTN3A1. HMBPP binding induces conformational changes, allowing for the formation of a BTN3A1/BTN2A1 heterodimer which increases affinity for the Vδ2Vγ9 T‐cell receptor (TCR). This induces the release of anti‐inflammatory cytokines such as IFN‐γ and TNF‐α. Natural killer receptors on the surface of Vδ2Vγ9 T cells can also be activated by stress‐induced ligands expressed by target cells, resulting in the release of perforins and granzymes. The figure was created using Biorender, adapted from Mensurado et al.

Figure 2

The pro (red) and anti‐tumour (green) roles of Vγ9Vδ2⁺ T cells and the cytokines involved in differentiation into various effector/regulatory functions following pAg‐induced activation., This figure is adapted from Imbert and Olive and Pang et al., and was created using Biorender.

Figure 3

Inhibitory receptors expressed by γδ T cells shown in conjunction with their corresponding ligands. The natural ligand for B and T lymphocyte attenuator (BTLA) is herpesvirus entry mediator (HVEM), CD80/86 expression can inhibit T‐cell activation via cytotoxic T‐lymphocyte‐associated protein 4, programmed cell death protein 1 (PD‐1) is inhibited by programmed cell death ligand 1 (PD‐L1) and killer cell Immunoglobulin‐like receptor (KIR2DL2/3) is associated with human leukocyte antigen I (HLA‐I). This figure is adapted from Gao et al., and was created using Biorender.

Figure 4

N‐BP mechanism of action whereby farnesyl pyrophosphate synthase (FPPS) is inhibited in the mevalonate pathway. FPPS is involved in the conversion of Isopentenyl Pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) which can be utilised for cholesterol synthesis. Accumulation of endogenous IPP can be detected by Vδ2Vγ9 T cells due to binding of IPP to the intracellular B30.2 domain of the transmembrane protein BTN3A1. This figure is adapted from Sanz et al., and was created using Biorender.

Figure 5

(a) Typical structure of simple liposomal nanocarriers which feature a phospholipid bilayer where hydrophobic drugs may be encapsulated and an aqueous core allowing for the encapsulation of hydrophilic molecules. Aminobisphosphonates (n‐BPs) are hydrophilic so are typically encapsulated within the core of the nanocarrier. (b) Leaky vasculature that is common to many solid tumours allows for the enhanced permeability and retention (EPR) effect meaning that small nanoparticles can extravasate from blood vessels into tumours and will not be drained by the lymph system due to impaired lymphatic drainage. This allows nanoparticles to passively accumulate at tumour sites. The figure was created using Biorender.