Function and Spatial Organization of Tumor-Invasive Human γδ T Cells-What Do We Know?

Human gammadelta (γδ) T cells not only infiltrate or reside in healthy tissues but also enter solid cancers. A large body of evidence suggests that γδ T cells can exert potent anti-tumor effects, although conflicting or unfavorable effects have been reported in some cancer entities. Infiltration patterns are key to understanding the complexity of the tumor microenvironment (TME) and its interplay with γδ T cells. The limited data available describe different γδ T cell subsets that are located in different areas around and within tumors. Tumor-infiltrating γδ lymphocytes (γδ TIL) exert cytotoxicity, for example, via the CD95- or TRAIL-axis, produce high amounts of granzymes, and after their activation, tumor necrosis factor (TNF)-α or IFN-γ and express immune checkpoint receptors. Under certain conditions, γδ T cell subsets can express low amounts of IL-17 and seem to contribute to immune regulation/suppression. A polarization of γδ T cells can be influenced by the TME. Inflammatory cytokines, growth factors, or tumor promoters can suppress γδ T cell functionality or even push them toward tumor promotion. To avoid this and to exploit the unique features of γδ T cell-mediated anti-cancer and immune-orchestrating capabilities in future immune therapy approaches, a growing body of preclinical but also clinical studies can be observed.