Controversial role of γδ T cells in pancreatic cancer.

γδ T cells are rare lymphocytes with cogent impact on immune responses. These cells are one of the earliest cells to be recruited in the sites of infection or tumors and play a critical role in coordinating innate and adaptive immune responses. The anti-tumor activity of γδ T cells have been numerously reported; nonetheless, there is controversy among published studies regarding their anti-tumor vs pro-tumor effect- especially in pancreatic cancer. A myriad of studies has confirmed that activated γδ T cells can potently lyse a broad variety of solid tumors and leukemia/lymphoma cells and produce an array of cytokines; however, early γδ T cell-based clinical trials did not lead to optimal efficacy, despite acceptable safety. Depending on the local micromilieu, γδ T cells can differentiate into tumor promoting or suppressing cells such as Th1-, Th2-, or Th17-like cells and produce prototypical cytokines such as interferon-γ (IFNγ) and interleukin (IL)-4/-10, IL-9, or IL-17. In an abstruse tumor such as pancreatic cancer- also known as immunologically cold tumor- γδ T cells are more likely to switch to their immunosuppressive phenotype. In this review we will adduce the accumulated knowledge on these two controversial aspects of γδ T cells in cancers- with a focus on solid tumors and pancreatic cancer. In addition, we propose strategies for enhancing the anti-tumor function of γδ T cells in cancers and discuss the potential future directions.