The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy

Abstract

γδ T cells are a distinct subset of T cells whose T cell receptors consist of γ chains and δ chains, different from conventional αβ T cells. γδ T cells are considered as a member of the innate immunity because of their non-MHC restricted antigen recognition, rapid response to invading pathogens and sense early changes of malignant cells. Upon activation, they can further promote the activation of adaptive immune cells, such as T cells and B cells, by secreting various cytokines. Thus, γδ T cells are regarded as a bridge between innate immunity and acquired immunity. γδ T cells are involved in a variety of immune response processes, including immune defense and immune surveillance against infection and tumorigenesis. γδ T cells recognize multiple tumor-associated antigens or molecules in T cell receptors (TCRs)-dependent and natural killer cell receptors (NKRs)-dependent ways. γδ T cells not only display a direct killing capacity on a variety of tumors, but also exert anti-tumor immune responses indirectly by facilitating the function of other immune cells, such as dendritic cells (DCs), B cells and CD8⁺ T cells. In this review, we summarize the major subpopulations, the tumor recognition mechanisms, and the anti-tumor effects of human γδ T cells, particularly the potential of γδ T cells for cancer immunotherapy.

Keywords: anti-tumor effect; cancer immunotherapy; γδ T cells.

Figure 1

The tumor cell recognition of γδ T cells. γδ T cells recognize tumor cells through γδ TCRs and NKRs. Vγ9Vδ2 TCR recognizes pAg (such as IPP) depending on BTN3A1 and BTN2A1. Besides, Vγ9Vδ2 T cells also recognize tumor cells through NKG2D and DNAM-1, which engage with their ligands (MICA/B, ULBPs and Nectin-2, PVR). Vγ9Vδ2 T cells express CD16 that binds therapeutic antibodies to engage Vγ9Vδ2-mediated ADCC. Vδ1 T cells recognize lipid antigen-presented by CD1d through Vδ1 TCR. NKG2D and NCRs (NKp30, NKp44, NKp46) with their ligands are involved in the tumor cell recognition by Vδ1 T cells. In addition, EPCR as a ligand of Vγ4Vδ5 TCR is involved in the tumor cell recognition by Vγ4Vδ5 T cells. TCRs: T cell receptors; NKRs: natural killer cell receptors; pAg: phosphoantigen; IPP: isopentenyl pyrophosphate; BTN3A1: butyrophilin 3A1; BTN2A1: butyrophilin 2A1; DNAM-1: DNAX accessory molecule 1; PVR: polyoma virus receptor; MICA/B: MHC class I-related chain A/B; ULBPs: UL16-binding proteins; ADCC: antibody-dependent cell-mediated cytotoxicity; NCRs: natural cytotoxicity receptors; EPCR: endothelial protein C receptor.