Current advances in ?? T cell-based tumor immunotherapy

gdT cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of gd T cells: those that express Vd1 gene, paired with different V? elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, ?? T cells expressing the Vd2 gene paired with the Vg9 chain are the predominant (50-90%) gd T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote ?? T cell activation. ?? T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that aß T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-? and tumor necrosis factor-a and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of gd T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of gd T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded gd T cells, particularly the Vg9Vd2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that gd T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the gd T cell-based immunotherapy of cancer.