Current Advances in γδ T Cell-Based Tumor Immunotherapy

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.

TCR Sequencing Reveals the Distinct Development of Fetal and Adult Human Vγ9Vδ2 T Cells

“…T cells after infusion of these stimulants have not yet been solved (10)(11)(12). In addition, it is difficult to expand ex vivo Vγ9Vδ2 T cells from advanced cancer patients with decreased initial numbers of peripheral blood Vγ9Vδ2 T cells (11).…”

“…These phosphoantigens do not bind directly the Vγ9Vδ2 TCR but have been recently shown to be sensed by the butyrophilin BTN3A1 and, via a mechanism that is yet to be fully understood, activate indirectly the Vγ9Vδ2 T cells (8,9). The recognition of phosphoantigens allows Vγ9Vδ2 T cells to develop potent antimicrobial immune responses or to promote the killing of transformed host cells that up-regulate IPP production, which has led to the development of clinical trials targeting Vγ9Vδ2 T cells as a cancer immunotherapy approach (4,(10)(11)(12).…”

Induction of Antitumor Immunity by Exosomes Isolated from Cryopreserved Cord Blood Monocyte-Derived Dendritic Cells

“…Based on these functions, CD3 + CD8 + T cells became a potential target in immune cell therapy for cancer treatment. Recently, CD3 + Vγ9 T cell population was shown to possess many antitumor characteristics in both in vitro [39][40][41] and in vivo studies [42][43][44], which enable them to have anti-tumor factors. However, the number of CD3+Vγ9 T cell population is rather small and accounted for less than 5% in peripheral blood [45,46].…”

In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

“…The unique features of γδ T cells, such as their capability to directly recognize antigens, efficiently produce cytokines and lyse tumor cells, as well as their ability to effectively orchestrate the network of effector cells, related to their key roles in immune surveillance and protective immunity, make γδ T cells ideal candidates to establish long-lasting immunity against pathogenic invaders and cancers. Accordingly, efforts to harness γδ T cells for clinical contexts, mostly by the adoptive transfer of ex vivo activated and expanded γδ T cells, have been tested for various types of cancers, but most trials have resulted in limited clinical efficacy [3][4][5][6][7][8][9][10][11].…”