Potential of human γδ T lymphocytes for immunotherapy of cancer

T lymphocytes are classified into 2 subsets based on their T‐cell receptor (TCR) expression. The vast majority of T cells expresses an αβ TCR heterodimer. These αβ T cells recognize antigenic peptides presented by MHC class I (for CD8 + T cells) or MHC class II molecules (for CD4 + T cells). Concepts of cancer immunotherapy are mostly concerned with activation of these MHC‐restricted αβ T cells. Until recently, a numerically small subset of T cells, which expresses an alternative TCR composed of a CD3‐associated γδ heterodimer, has received far less attention as a potential agent in cancer therapy. These γδ T cells share with αβ T cells certain effector functions such as cytokine production and potent cytotoxic activity but recognize different sets of antigens, usually in a non‐MHC‐restricted fashion. Different subsets of human γδ T cells recognize stress‐inducible MHC class I‐related molecules frequently expressed on epithelial tumor cells or phosphorylated metabolites which can be generated by tumor cells. In line with this, many tumor cells are highly susceptible to γδ T‐cell mediated lysis. In our article, we summarize the available evidence for a contribution of human γδ T cells in tumor defense and discuss potential strategies for the immunotherapy of tumors based on the endogenous activation and/or adoptive transfer of tumor‐reactive γδ T lymphocytes. © 2004 Wiley‐Liss, Inc.