Cancer immunotherapy with γδ T cells: many paths ahead of us

gamma delta T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human gamma delta T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional alpha beta T cells. V gamma 9V delta 2 gamma delta T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. gamma delta T cells expressing other T cell receptor variable genes, notably V delta 1, are more abundant in mucosal tissue. In addition to the T cell receptor, gamma delta T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, gamma delta T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of gamma delta T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of gamma delta T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of gamma delta T cells, the optimization of in vitro expansion protocols, and the development of gene-modified gamma delta T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.