γδ T cells in hematological malignancies: mechanisms and therapeutic strategies

Abstract

γδ T cells are a unique subset of lymphocytes with both innate and adaptive features. They recognize and eradicate various hematological malignancies through different mechanisms, employing factors including γδ TCR, NKR, NKG2D, TRAIL, and perforin/granzyme. They also modulate other immune cells to enhance their antitumor activity. Moreover, γδ T cells have potent antiviral functions after hematopoietic stem cell transplantation (HSCT), which may improve the outcome of patients with hematological malignancies. In this review, we summarize the current knowledge on γδ T cell biology and function in hematological malignancies and HSCT complications. We also discuss the challenges and limitations of the clinical application of γδ T cells, such as their low frequency in peripheral blood and heterogeneity among different subsets. We then highlight some promising strategies for γδ T cell-based therapy, such as using agonist antibodies, cell engagers, or genetic modification technology. Furthermore, we review the recent clinical trials evaluating the safety and efficacy of γδ T-cell therapy in different hematological malignancies. In conclusion, γδ T cells represent a promising immunotherapeutic tool for hematological malignancies that deserves further exploration.

Keywords: Hematological malignancies; Immune cell therapy; γδ T.

Figure 1.

γδ T cell development. The diagram depicts the development of γδ T cell and αβ T cell from bone marrow progenitors. They originate from common thymic precursors and branch from DN3 thymocytes stage. Functional expression of αβ TCR or γδ TCR drives cells into αβ T or γδ T cell lineage. αβ T cells which undergo positive and negative selection are mature and eventually migrate to periphery and second lymphoid organ. While γδ T cells gain IL-17 or IFN-γ-producing properties through different transcriptional factor signal and ultimately migrate to peripheral blood or tissues. IFN-γ = interferon-γ, IL-17 = interleukin 17, TCR = T-cell receptor.

Figure 2.

The functions of γδ T cells. Human γδ T cells exhibit potent cytotoxicity against various tumors through multiple mechanisms, such as receptor-ligand interactions (eg, γδ TCR, NKR, TRAIL, and FasL), cytokine secretion (eg, IFN-γ, TNF-α) and release of cytolytic granules (eg, granzyme B and perforin). They can also mediate ADCC against tumor cells. Furthermore, they can modulate anticancer immunity by interacting with other immune cells, such as B cells, NK cells, and αβ T cells. In particular, Vδ2-negative T cells have been shown to play a crucial role in controlling CMV and EBV infections after HSCT, as they can recognize viral particles or infected cells via TLRs, γδTCRs, and NKG2D, and exert antiviral effects by producing IFN or lysing infected cells directly or indirectly through cross-talk with other immune cells. The role of γδ T cells in GvHD is still unclear, but some studies have reported that γδT17 and Vγ4 T cells could ameliorate GvHD in mouse models. ADCC = antibody-dependent cellular cytotoxicity, CMV = cytomegalovirus, EBV = Epstein–Barr virus, FasL = Fas ligand, GvHD = graft-versus-host disease, GZMB = granzyme B, HSCT = hematopoietic stem cell transplantation, IFN-γ = interferon-γ, NKG2D = natural killer group 2-member D, TCR = T-cell receptor, TLR = toll-like receptor, TNF-α = tumor necrosis factor α, TRAIL = tumor necrosis factor-related apoptosis-inducing ligand. Figures are created with Biorender.com.