Human gamma delta T regulatory cells in cancer: fact or fiction?

While gamma delta T cell (γδTc) anticancer immunotherapies are being developed, recent reports suggest a regulatory role for γδTc tumor-infiltrating lymphocytes. This mini-review surveys available evidence, determines strengths and weaknesses thereof and suggest directions for further exploration. We focus on human γδTc, as mouse and human γδTc repertoires differ. Regulatory γδTc are defined and compared to conventional Tregs and their roles in health and disease (focusing in on cancer) are discussed. We contrast the suggested regulatory roles for γδTc in breast and colorectal cancer with their cytotoxic capabilities in other malignancies, emphasizing the context dependence of γδTc functional plasticity. Since γδTc can be induced to exhibit regulatory properties (in some cases reversible), we carefully scrutinize experimental procedures in published reports. As γδTc garner increasing interest for their therapeutic potential, it is critical that we appreciate the full extent of their role(s) and interactions with other cell types in both the circulation and the tumor microenvironment. A comprehensive understanding will enable manipulation of γδTc to improve anti-tumor efficacy and patient outcomes.