γδ T cells in cancer: a small population of lymphocytes with big implications

Abstract

γδ T cells are a small population of mostly tissue-resident lymphocytes, with both innate and adaptive properties. These unique features make them particularly attractive candidates for the development of new cellular therapy targeted against tumor development. Nevertheless, γδ T cells may play dual roles in cancer, promoting cancer development on the one hand, while participating in antitumor immunity on the other hand. In mice, γδ T-cell subsets preferentially produce IL-17 or IFN-γ. While antitumor functions of murine γδ T cells can be attributed to IFN-γ⁺ γδ T cells, recent studies have implicated IL-17⁺ γδ T cells in tumor growth and metastasis. However, in humans, IL-17-producing γδ T cells are rare and most studies have attributed a protective role to γδ T cells against cancer. In this review, we will present the current knowledge and most recent findings on γδ T-cell functions in mouse models of tumor development and human cancers. We will also discuss their potential as cellular immunotherapy against cancer.

Keywords: CAR T‐cells; DOT cells; antitumor immunity; immunotherapy; tumor progression; γδ T cells.

Figure 1

γδ T cells express an array of activating receptors for tumor cell recognition. Many of these mechanisms rely on the upregulation of stress ligands by tumor cells, including MICA/B (humans), Rae‐1/H‐60 (mouse) and ULBPs. γδ T cells also display an NK‐like phenotype in their expression of NCRs (NKp30, NKp44 and NKp46), particularly following activation. LFA‐1, lymphocyte function‐associated antigen 1; NKG2D, natural killer group 2 member D; PLZF, promyelocytic leukaemia zinc finger protein; Rae1, retinoic acid early inducible‐1; TCR, T‐cell receptor; TRAIL, TNF‐related apoptosis‐inducing ligand; ULBP, UL16‐binding proteins. * denotes expression on some clones only.

Figure 2

Pro‐ and antitumor effect of γδ T cells. (1) Antitumor immunity of γδ T cells by direct killing of tumor cells via perforin, granzymes, granulysin and cytokines. (2) Vγ5+ γδ T cells induce B‐cell class switching to autoreactive antitumor IgE. (3) IFN‐γ production by γδ T cells promotes the recruitment of NK, Th1 and CTLs and induces the differentiation of antitumor macrophages. Additionally, IFN‐γ enhances the presentation capacities of APCs and MHC I expression by tumor cells, while inhibiting pro‐tumor T helper cells. (4) γδ T cells producing IL‐17 promote angiogenesis and suppress antitumor CTL and Th1 cells. (5) Production of IL‐22 and amphiregulin by γδ T cells induces direct tumor cell proliferation. The dashed line separates mouse and human γδ T cells. γδ T cells depicted in red are the cells with antitumor functions, while γδ T cells depicted in green are the cells that promote tumor growth.