Abstract
γδ T 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 γδ T cells: those that express Vδ1 gene, paired with different Vγ 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, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50–90%) γδ 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 γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that αβ T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-γ and tumor necrosis factor-α and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ 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 γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ 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 γδ T cell-based immunotherapy of cancer.
Highlights
T cells carrying the γδ T cell receptor (TCR) are a minor lymphocyte population that accounts for 2–5% of CD3 T cells in the peripheral blood, but predominate in several anatomic sites such as the intestine and the skin
A second group of nine patients was selected for in vitro Vγ9Vδ2 T cell response to Pamidronate and IL-2 and was treated with Pamidronate followed by increasing doses of IL-2
The treatments were well tolerated and a significant clinical response was observed in the group receiving Zoledronate and IL-2 during the 1-year follow-up, which correlated with sustained elevated numbers of blood Vγ9Vδ2 TEM cells producing IFN-γ and TNF-related apoptosis-inducing ligand (TRAIL)
Summary
T cells carrying the γδ T cell receptor (TCR) are a minor lymphocyte population that accounts for 2–5% of CD3 T cells in the peripheral blood, but predominate in several anatomic sites such as the intestine and the skin. PAgs are synthesized in mammalian cells through the mevalonate pathway [5], but PAg concentrations required for Vγ9Vδ2 T cell activation are not achieved in physiological conditions, but only after infections or tumor transformation [6] From this point of view, the Vγ9Vδ2 TCR works in a similar way to a pattern-recognition receptor, which senses metabolic changes found in transformed or infected cells. Vγ9Vδ2 T cells recognize via their TCR non-peptidic phosphoantigens (PAgs) and BTN3A1, while Vδ1 T cell receptor (TCR) ligands are not defined yet Both γδ T cell subsets constitutively express surface natural cytotoxicity cell receptors (NCRs) that bind MICA/MICB and ULBPs, frequently expressed on tumor cells. We will review the major achievements and pitfalls of the Vγ9Vδ2 T cell-based immunotherapy
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