Potential of human γδ t lymphocytes for immunotherapy of cancer

Abstract

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 αβT 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.