Gamma-delta (γδ) T cells: friend or foe in cancer development?

Abstract

Background: γδ T cells are a distinct subgroup of T cells containing T cell receptors (TCRs) γ and TCR δ chains with diverse structural and functional heterogeneity. As a bridge between the innate and adaptive immune systems, γδ T cells participate in various immune responses during cancer progression. Because of their direct/indirect antitumor cytotoxicity and strong cytokine production ability, the use of γδ T cells in cancer immunotherapy has received a lot of attention over the past decade.

Main text: Despite the promising potential of γδ T cells, the efficacy of γδ T cell immunotherapy is limited, with an average response ratio of only 21%. In addition, research over the past 2 years has shown that γδ T cells could also promote cancer progression by inhibiting antitumor responses, and enhancing cancer angiogenesis. As a result, γδ T cells have a dual effect and can therefore be considered as being both "friends" and "foes" of cancer. In order to solve the sub-optimal efficiency problem of γδ T cell immunotherapy, we review recent observations regarding the antitumor and protumor activities of major structural and functional subsets of human γδ T cells, describing how these subsets are activated and polarized, and how these events relate to subsequent effects in cancer immunity. A mixture of both antitumor or protumor γδ T cells used in adoptive immunotherapy, coupled with the fact that γδ T cells can be polarized from antitumor cells to protumor cells appear to be the likely reasons for the mild efficacy seen with γδ T cells.

Conclusion: The future holds the promise of depleting the specific protumor γδ T cell subgroup before therapy, choosing multi-immunocyte adoptive therapy, modifying the cytokine balance in the cancer microenvironment, and using a combination of γδ T cells adoptive immunotherapy with immune checkpoint inhibitors.

Keywords: Adoptive immunotherapy; Antitumor; Cytokine; Polarization; Protumor; Tumor microenvironment; γδ T cells.

Fig. 1

Classification of γδ T cells towards tumors. Vδ1 γδ T cells and Vδ2 γδ T cells are normal resting γδ T cells before activation or polarization. Following stimulation with different cytokines, resting γδ T cells can polarize into the protumor subgroups: FoxP3+ γδ Treg, γδ T17, or become activated Vδ1 γδ T cells. In addition, resting γδ T cells can also polarize into the antitumor subgroup: γδ Tfh, and γδ T1, or become activated Vδ1 γδ T cells

Fig. 2

Antitumor and protumor functions of γδ T cells. γδ T cells have both direct and indirect antitumor effects. Direct antitumor effects are mediated by lysing the tumor through the perforin-granzyme pathway, providing an early source of the inflammatory cytokines such as IFN-γ and TNF-α, eliminating Fas+ and TRAIL-R+ tumor cells, and ADCC. The indirect antitumor role of γδ T cells is mediated by polarized γδ Tfh cells, which promote B-cell antibody secretion. Besides, γδ T cells also present antigens for αβ T cell priming, trigger dendritic cell (DC) maturation, and induce robust NK cell-mediated antitumor cytotoxicity to play indirect antitumor role. With regard to their protumor effect, γδ T cells can polarize into FOXP3+ γδ Treg cells, and γδ T17 cells. In addition, Vδ1 T cells are another subset of γδ T cells that possess protumor activity. γδ T cells are able to directly impair αβ T cells and DC antitumor immunocyte function. γδ T cells can also enhance MDSC, SPM, and neutrophil immunosuppressive functions. Together, these actions promote tumor angiogenesis, growth, proliferation, metastasis, and immune escape

Fig. 3

The functions of γδ T cells are influenced by the TME. The balance of pro- and anti-inflammatory cytokines and the cellular state govern the function of γδ T cells. Tumor and stromal cells produce a variety of cytokines and chemokines that either contribute to or disrupt the development of a pro-tumorigenic niche. These factors can also reprogram γδ T cells to adopt a protumor or antitumor state