Subscribe
  • Original Article
  • OPEN ACCESS

Immune Regulatory Networks and Therapy of γδ T Cells in Liver Cancer: Recent Trends and Advancements

  • Kun-Li Yin1,#,
  • Kai-Jian Chu2,#,
  • Ming Li1,
  • Yu-Xin Duan1,
  • Yan-Xi Yu1,
  • Mei-Qing Kang1,
  • Da Fu3,*  and
  • Rui Liao1,* 
 Author information
Journal of Clinical and Translational Hepatology 2024;12(3):287-297

DOI: 10.14218/JCTH.2023.00355

Abstract

The roles of γδ T cells in liver cancer, especially in the potential function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines, have aroused research interest. This review briefly describes the basic characteristics of γδ T cells, focusing on their diverse effects on liver cancer. In particular, different subtypes of γδ T cells have diverse or even opposite effects on liver cancer. We provide a detailed description of the immune regulatory network of γδ T cells in liver cancer from two aspects: immune components and nonimmune components. The interactions between various components in this immune regulatory network are dynamic and pluralistic, ultimately determining the biological effects of γδ T cells in liver cancer. We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment, emphasizing the potential of these cells in liver cancer immunotherapy.

Keywords

Liver cancer, γδ T cells, Immunotherapy, Tumor microenvironment

Introduction

Liver cancer, as a globally notorious malignant tumor, causes hundreds of thousands of deaths and poses a serious socioeconomic burden.1,2 The pathogenesis of liver cancer is unclear and is inseparable from its complex tumor microenvironment (TME).3 The protumor/antitumor factors or cellular/noncellular components form a multicellular network in the TME, collectively determining the malignant biological behaviors of liver cancer cells.4–7 Since patients with liver cancer are often diagnosed in the middle to late stages, most patients lose the opportunity for surgical radical resection and face a poor prognosis.8 Notably, immunotherapy has significantly improved the treatment of liver cancer.9–11 Cellular immunotherapy, involving natural killer cells (NKs),12,13 chimeric antigen receptor T cells (CAR-T cells),14,15 and γδ T cells, is emerging as a star in the field of immunotherapy, with its efficacy confirmed by various of mechanistic studies and clinical research.

γδ T cells belong to the innate but nonconventional lymphocyte family, constituting approximately 5% (on average) of total T cells in peripheral blood.16–18 γδ T cells, comprising 15–25% of the total liver T cells, are 5–10 times more abundant in the liver than in other tissues and organs.19 Moreover, hepatic γδ T cells are highly localized in the liver, exhibiting a more active and mature phenotype with high CD44 and low CD62 markers.20 In the thymus, “double negative” (DN) thymocytes, the primary immature precursors of γδ T cells, undergo rearrangement after α-selection, β-selection, γ-selection and δ-selection. Following TCR γδ signal stimulation,21 TCR γδ+ DN progenitors are directed into the γδ T-cell lineage and subsequently differentiate and mature into γδ T cells.22,23 Additionally, the gene expression profile reveals that the gene signatures of γδ T cells are equivalent to those of a mixture of αβ T cells and NK cells, endowing γδ T cells with the characteristics of both cell types.24 Compared with αβ T cells, γδ T cells typically exhibit different immune phenotypes. Besides the common expression of CD2, CD3, CD5, and CD7, γδ T cells are usually negative for CD4 and CD8, with occasional CD8 positivity.25 Although they both express CD3, the expression level is higher in γδ T cells than in αβ T cells.26 The most notable distinction from αβ T cells is that γδ T cells are not restricted by major histocompatibility complex (MHC) molecules,27 enabling them to be activated within minutes to detect molecular signals stimulated by infection or cancer and subsequently produce a large number of proinflammatory cytokines and chemokines.21,28

Much research attention is promptly focused on understanding the relationship between γδ T cells and tumors, as well as the therapeutic prospects of γδ T cells in antitumor activities. Here, we summarize the functional plasticity of γδ T cells and their dual role in liver cancer. We also discuss the immune regulatory networks of γδ T cells involved in the microenvironment of liver cancer, γδ T-cell-based immunotherapy in liver cancer and perspectives on its development and use in the future.

Subtypes of γδ T cells and pathophysiological roles

Classification of γδ T Cells

Human γδ T cells are usually divided into Vδ1+, Vδ2+, and Vδ3+γδ T cells according to the difference in the arrangement of the γ chain and δ chain.29 Vδ1+γδ T cells are mainly distributed in the epithelium and mucosa, accounting for approximately 5–10% of γδ T cells.30,31 Vδ2+γδ T cells are mainly present in peripheral blood, constituting the majority of the total number of γδ T cells. In particular, γδ T cells expressing the Vγ9Vδ2 TCR account for 50–95% of total γδ T cells and are also the main cells responsible for the antitumor effects.32 Vδ3+ γδ T cells are mainly present in the liver and small intestine epithelium. There is relatively little research on the role of Vδ3+ γδ T cells in tumors, but there is still research potential.33,34 Furthermore, Vδ1+ γδ T cells and Vδ2+ γδ T cells can be further classified by the expression of different CD molecules and the skewed expression patterns of the memory markers CD45RA and CD27. Vδ1+ γδ T cells from healthy individuals mainly represent a CD45RA+CD27+ phenotype,35 with high expression of CD56.36 However, Vδ1+γδ T cells in tumor tissue tend to exhibit a CD45RA-CD27- phenotype.37,38 Vδ2+ γδ T cells mainly exhibit a CD45RA- CD27+ phenotype, with CCR5 and CD161 generally overexpressed, allowing them to quickly migrate to inflammatory tissue.36 Accordingly, γδ T cells display subset-specific features that need to be emphasized, as these features increase the understanding of the true role of γδ T cells in different diseases, especially their role in cancer.

Pathophysiological roles of γδ T cells

γδ T cells exert an extensive array of biological effects. Their main characteristics include cytotoxic activity against target cells and the secretion of different types of cytokines and chemokines. γδ T cells can also interact with other cells, such as αβ T cells, dendritic cells (DCs), B cells, NKs and macrophages. Through these functional activities, γδ T cells exhibit anti-infection and antitumor effects and play a role in immune regulation and damage repair.

Numerous studies have revealed that γδ T cells exert their antitumor effect mainly through the production of cytokines (such as interferon γ (IFN γ) and TNF-α), triggering γδ TCR recognition molecules, NK cell receptors (NKRs), and antibody-dependent cell-mediated cytotoxicity (ADCC). The recognition of γδ TCR depends on interactions with specific phosphoantigens,39–41 such as butyrophilin 3 A1 (BTN3A1),42 and subsequently activating Vγ9Vδ2 T cells. BTN2A1 is essential for BTN3A1-dependent Vg9Vd2 T-cell activation against cancer cells, regulating Vγ9Vδ2 T-cell binding to the TCR.43 Representative molecules of the NK recognition mechanism include NKG2D,44 NKp30,45 and NKp44.45 Various cytokines and chemokines assist γδ T cells in achieving cytotoxic functions while acting as regulators in the immune microenvironment. Some scientific evidence indicates that γδ T cells exhibit cytotoxic activity in liver cancer46–48 and are under the regulation of cytokines such as IL-2 and IL-21.49 Additionally, IL-17 and IL-2, the most common cytokines secreted by γδ T cells, have been identified as biomarkers of poor prognosis in malignant tumors, related to the maintenance and promotion of the inflammatory environment.50,51 γδ T cells are the main providers of IFN γ in tumor immunity, and IFN γ plays an crucial role in controlling tumor development.52,53 Currently, it is acknowledged that the chemokines produced by γδ T cells include C-C chemokine receptor (CCR)2,54 CCR5,55 CCR6,56 CCR7,57 and CCR9,55 which play an auxiliary role in γδ T cell anti-infection and antitumor functions. The recruitment and activation of γδ T cells depend on the reactivity of different chemokine signals. Chemokines induce γδ T cells to accurately migrate to the desired site, and γδ T cells and other cells produce chemokines, achieving this goal together.

Elucidating the interactions between γδ T cells and other immune cells will increase the understanding of γδ T cells. γδ T cells have been confirmed to function as antigen-presenting cells (APCs), similar to DCs, effectively processing and presenting antigens to CD4+ T cells and CD8+ T cells to initiate immune responses.58 Furthermore, γδ T cells provide strong stimulation signals for the differentiation and maturation of DCs through the Fas-Fas L pathway.59,60 Another study found that γδ T cells and DCs mutually promote maturation, and the increase in DC-induced apoptosis induces the expression of γδ T-cell ligands, thereby activating γδ T cells.59 The proliferation and differentiation of αβ T cells are still induced by γδ T cells,61 but in the tumor microenvironment, γδ T cells show an inhibitory effect on the activation of αβ T cells and support the occurrence of pancreatic tumors.62 It has been proven that Vδ2+ and Vδ3+γδ T cells affect the differentiation, antibody secretion, and cytokine production of B cells, starting from the moment that B cells are released from the bone marrow.63,64 γδ T cells are associated with changes in the number of macrophages, and they also promote M2 macrophage polarization by secreting IL-17A, thus contributing to the clearance of infected cells.65 Additionally, the number of peripheral γδ T cells is negatively correlated with the accumulation of neutrophils and M1 macrophages. Peripheral γδ T cells limit the expansion and recruitment of neutrophils to alleviate inflammation.66,67 In a liver ischemia–reperfusion injury model, γδ TCR and IL-17a contribute to the increase in neutrophil numbers and exacerbate liver injury.68 It is thus clear that the relationships between γδ T cells and other immune cells are extensive and far-reaching, shaping the body’s vast immune regulatory network. The subtypes of γδ T cells and the pathophysiological roles of γδ T cells in tumors are summarized in Figure 1.

The subtypes of γδ T cells and the pathophysiological roles of γδ T cells in tumors.
Fig. 1  The subtypes of γδ T cells and the pathophysiological roles of γδ T cells in tumors.

Human γδ T cells are usually divided into Vδ1+, Vδ2+, and Vδ3+γδ T cells according to the arrangement of the γ chain and δ chain. Vδ1+ γδ T cells and Vδ2+ γδ T cells can be further classified by the expression of the memory markers CD45RA and CD27. The pathophysiological roles of γδ T cells include their cytotoxic activity against target cells, the secretion of different types of cytokines and chemokines and their interaction with other cells, such as αβ T cells, dendritic cells (DCs), B cells, natural killer cells (NKs), and macrophages. DCs, dendritic cells; NKs, natural killer cells. IFN-γ, interferon γ; CCR, C-C chemokine receptor; TNF-α, tumor necrosis factor-α; IL, interleukin; TCR, T cell receptor.

A dual role of γδ T cells in liver cancer

In the TME of liver cancer, the diversity of γδ T cell subpopulations in anti-tumor immune functions, such as the dynamic interactions between tumor promotion and inhibition, has received widespread attention, with special emphasis on the differences between Vδ 1+and Vδ2+ γδ T cells. The functional paradigm of γδ T cells and their secreted factors was defined in tumor immunity through an in-depth understanding of γδ T cell subpopulations, enabling these subpopulations to exert anti-tumor effects in the tumor microenvironment. However, the γδ T cell subpopulations and their corresponding tumor effects are still being refined. With the development of more experimental methods, the dual role and mechanism of γδ T cells in liver cancer will be elucidated in greater detail and accuracy, becoming the key to explaining immune tolerance in liver cancer. A dual role of γδ T cells in liver cancer is summarized in Figure 2.

A dual role of γδ T cells in liver cancer.
Fig. 2  A dual role of γδ T cells in liver cancer.

Different subtypes of γδ T cells have diverse or even opposite effects on liver cancer. IFN-γ, interferon γ; TGF-β, tumor growth factor-β; TNF-α, tumor necrosis factor-α; IL, interleukin; LAG3, lymphocyte activation gene-3; PD-1, programmed death -1; CD96, cluster of differentiation-96; ULBP1, ul16-binding protein; NKGD2, natural killer group member D.

Antitumor immunosurveillance in liver cancer

Studies using γδ T cells, particularly Vγ9Vδ2 T cells, to treat liver cancer have shown positive results. A high proportion of Vγ9Vδ2 T cells is associated with longer HCC patient survival times.69,70 NKRs expressed by γδT cells, especially the NKG2D receptor, are the main cell type that combats cancer.71 High expression of the NKG2D receptor is beneficial for enhancing the cytotoxicity of γδ T cells against HCC cell lines.72 The ULBP family, which binds to NKRs and is expressed by tumors, is involved in the recognition of tumor antigens by Vγ9Vδ2 T cells, and its expression level determines the susceptibility of Vγ9Vδ2 T-cell lysis.73,74 High ULBP1 expression is positively correlated with the degree of severity of HCC.75 In patients with HCC, ULBP1 deficiency is an independent risk factor for early recurrence and poor prognosis.72 After binding to NKG2D, the release of IFN-γ and TNF-α is induced to promote γδ T-cell cytolytic activity.76 γδ T cells are important sources of IFN-γ and TNF-α, which are known to inhibit tumor growth by specifically inducing apoptosis and inhibiting angiogenesis.77,78 γδ T cells expressing DNAX accessory molecule-1 (DNAM-1) and CD96 can more efficiently recognize Nectin-like-5 expressed on HCC cells and enhance the lysis of HCC cells, with a concomitant increase in IFN-γ production.79 In addition, research has found that CD96+ γδ T cells are released from the liver and circulate in the bloodstream, having an inhibitory effect on the progression of other tumors.80 Several reports have shown that the killing ability of γδ T cells against cancer cells is related to external factors. A co-culture system of zoledronate (ZOL),81 alendronate (ALD),82 or artesunate83 with γδ T cells can effectively activate γδ T cells and increase tumor susceptibility. The antitumor properties of γδ T cells have great clinical application value. Further in-depth research is still needed to determine how γδ T cells can increase their own efficacy and enhance their recognition of HCC cells.

Tumor-promoting tolerance in liver cancer

Some studies have revealed the protumor effects of γδ T cells. HCC-infiltrating γδ T cells are mainly composed of IL-17-producing Vδ1 γδ T cells,84 which play a role in promoting tumor proliferation,85 angiogenesis,86 metastasis87 and immunotherapy resistance.88 Vδ1 γδ T cells are considered tissue-resident cells that are significantly enriched in the liver.69 Tissue residence produces a local immune tolerance effect that can be maintained for a long time, which is becoming a key feature of antitumor protection.89 Further research has found that the Vδ1+ T-cell population, which highly expresses LAG3, negatively regulates the antitumor function of T cells through immune suppression.90 In the HCC mouse model, IL-17A was secreted mainly by Vγ4 γδ T cells, so replenishing Vγ4 γδ T cells promoted tumor growth by recruiting myeloid-derived suppressor cells (MDSCs) in a CXCL5/CXCR2-dependent manner and further inhibiting CD8+ T cells to enhance immune suppression.91 More recently, among HCC patients, the cytotoxicity of γδ T cells was significantly reduced, which is related to the expression of PD-1 in γδ T cells being significantly upregulated. Coincubation of γδ T cells leads to an increased proportion of PD-L1+ HCC cells, which is highly likely to enhance the immune escape of tumor cells.49 Interestingly, Vγ9Vδ2 T cells, also representing immunosuppressive properties, deviate into Th1-, Th17-, or Treg-like phenotypes depending on the environment and secrete immunosuppressive factors (IL-4, IL-17 or IL-10 and TGF-β) to inhibit T-cell proliferation and indirectly suppress tumor immunity.92,93 Thus, the tumor-promoting effect of γδ T cells on liver cancer is comprehensive. Weakening or inhibiting the antitumor effect of γδ T cells is both a challenge and an opportunity for liver cancer research.

Immune regulatory networks of γδ T cells involved in the microenvironment of liver cancer

Nonimmune component regulatory networks

The immune regulatory network of γδ T cells in liver cancer is extremely sophisticated and multivariant, of which nonimmune components are an important factor. Environmental factors, such as reactive oxygen species production,94 oxygen tension,95 and lipoprotein levels,95 have been proven to impact the expression of IFN γ and/or NKR in γδ T cells. He et al. used single-cell sequencing to explain the metabolic changes of HCC-infiltrating γδ T cells which are significantly inhibited in oxygen metabolism, lipid metabolism, and amino acid synthesis, and tilt towards glutamine-rich metabolism, providing nutrients for tumor cell metabolism.90 Combined with a genome-wide CRISPR screening of target cancer cells, another study found that the triggering of γδ T cells by BTN3A and BTN2A1 depended on AMP-activated protein kinase (AMPK), and demonstrated that γδ T cells are regulated by multiple layers of BTN3A, such as transcription, post-translational modifications, and membrane transport, further deepening our understanding of γδ T cell stress monitoring.96 The homeostasis of IL-17A-producing γδ T cells retained in the liver is regulated by palmitic acid and CD1d, a necessary lipid antigen.97 Moreover, apoptosis, ferroptosis, and pyroptosis significantly induce an immunosuppressive microenvironment in HCC, in which an imbalance in γδ T cells and an increase in the Vd1+/Vd2+ ratio are markers of poor prognosis in HCC patients.98 Several reports have shown that the tumor-killing ability of γδ T cells is related to external factors. Artesunate enhances the antitumor function of γδ T cells by upregulating the expression of Fas on HepG2 cells while reducing the secretion of TGF-β by HepG2 cells, thus reversing the immune escape of HepG2 cells.83 The co-cultivation of zoledronate and HCC cell lines also resulted in an increase in the number and killing ability of γδ T cells.99 Overexpression of miR-382 in normal liver cells increases the sensitivity of γδ T cells to HCC, thereby promoting HCC cell lysis.100 Macrophage-stimulating protein (MSP) and peptide HP1 stimulate Vγ9Vδ2 T cells, which have high expression levels of IFN-γ and TNF-α, to exert a Th1-biased immune response for inhibiting HCC.46 Other cellular components in the liver, such as hepatic stellate cells, activate TLR3 under the mediation of exosomes, thereby increasing γδ T cell-mediated production of IL-17A, which exacerbates liver fibrosis.101 Evidently, the importance of γδT cell and cellular component interactions in elucidating the mechanism of liver cancer has begun to be recognized.102

Immune cellular regulatory networks

Crosstalk between γδ T cells and other immune cells, such as neutrophils, macrophages, T cells, and B cells, is widespread and has been identified in many malignant tumors. The immune balance in liver cancer is the result of γδ T cell self-regulation and their interactions with other immune cells. Tumor-infiltrating γδ T cells respond to signals from microorganisms and tumors, activate CD4+ and CD8+ T cells,103 and regulate the number and function of CD4, CD8, and NK cells.90 The activation of CD8+ T cells by γδ T cells may be achieved through the scavenger receptor CD36, resulting in tumor antigen-specific CD8+ T-cell responses.104 The regulation between different immunocytes is often bidirectional, but the effect of CD4+, CD8+, and NK cells on γδ T cells has not yet been revealed. The elucidation of these effects will help clarify the mechanism of γδ T cells in liver cancer and even other diseases. IL-17A produced by HCC-infiltrating Vγ4 γδ T cells enhances the infiltration of MDSCs, leading to the inhibition of the CD8+ T-cell response and the promotion of tumor growth.91 Additionally, MDSCs also harbor the capacity to modulate the generation of IFN-γ and the antitumor effect of Vδ2 γδ T cells in the tumor microenvironment.105 Moreover, TEM results have shown that there is a negative correlation between the number of γδ T cells and the number of Treg cells in HCC, possibly because CD4+CD25+ regulatory T cells directly suppress the cytotoxic function and IFN-γ secretion of γδ T cells in a TGF-β- and IL-10-dependent manner.106 On the other hand, γδ T cells can differentiate into γδ Treg cells and play an immunosuppressive role in cancer, as tumor-derived γδ Treg cells promote T cell and DC senescence through TLR8 signaling. This results in the inhibition of innate and adaptive immunity to maintain tumor suppression.107,108 To date, there is limited research evidence for the interaction between γδ T cells and other immune cells in liver cancer, which can help elucidate the occurrence and development of the liver. The relationships between γδ T cells and other immune or nonimmune cells in liver cancer are worth further exploration.

Immune molecular regulatory networks

Immune molecules are both executors and regulators of γδ T cell function. Relying on various immune molecules, γδ T cells successfully interact with other cells to construct a meticulous and efficient regulatory network in the liver cancer microenvironment. The high expression of CCR1/CCR5 makes γδ T cells recruited by C-C motif chemokine ligand 4 (CCL4)/CCL5 into HCC tissue, exerting protective effects on CD8+ T cells and strengthening the body’s antitumor ability.109 Another study pointed out that the high expression of CCR5 is a selective feature of Vδ2/Vγ9 γδ T cells, which is consistent with the shift in antitumor ability.110 Blockade of the CCL2/CCR2 axis has been considered a novel protective factor during the recruitment of Vδ1 T cells to HCC lesions.54,111 Furthermore, mutual crosstalk between chemokines and cytokines should be emphasized, which serves as a feedback mechanism that determines the final performance of γδ T cells in liver cancer.112,113 The binding of CCR6 and CCL20 significantly aggregates IL-17- and IL-22-expressing γδ T cells in damaged liver cells, which promotes the apoptosis of hepatic stellate cells (HSCs) involving Fas ligands, preventing the liver from entering an inflammatory and fibrotic state.114

For the interleukin family, TNF-α and INF-γ are both produced by and act upon γδ T cells. For example, the decrease in the cytotoxicity of γδ T cells in the blood circulation of HCC patients may be explained by the fact that the levels of some pro-inflammatory cytokines (IL-2 and IL-21) are reduced and PD-1 is upregulated.49 Moreover, tumor-infiltrating Vγ1 γδ T cells produce IL-4, which significantly reduces the expression levels of NKG2D, perforin-1, and IFN-γ in Vγ4 γδ T cells, diminishing cytotoxicity and reducing antitumor function.115 IL-35, an immunosuppressive cytokine, is produced by Treg cells in the hepatic microenvironment, and its overexpression promotes the depletion of γδ T cells and impairs their antitumor function in HCC.116 However, the influence of PD-1 expression on γδ T cells is not well defined. In hematological tumors, the blockade of PD-1 does not directly affect the cell-dependent lysis ability of γδ T cells, but PD-1+ γδ T cells produce more IFN-γ to enhance their own lethality.117 Similarly, IL-17A production from γδ T cells can be inhibited by high expression of PD-1 while reducing organ inflammation damage and immune resistance.88,118 Other studies contradict the above viewpoints, suggesting that high numbers of PD-1+ γδ T cells are correlated with a poor prognosis for patients with acute leukemia.119 In HCC cell lines, the cytotoxicity of PD-1+ γδ T cells is weakened.49 Deeper exploration of the relationship between γδ T cells and PD-1 expression will lead to a more comprehensive understanding of immunotherapy. Thus, the immunoregulatory balance of γδ T cells involved in liver cancer is not yet completely understood, but the joint forces of multiple cytokines, chemokines, and immunocytes determine the overall performance of γδ T cells in liver cancer. Brief summary of immune regulatory networks of γδ T cells involved in the microenvironment of liver cancer is summarized in Figure 3.

Brief summary of immune regulatory networks of γδ T cells involved in the microenvironment of liver cancer.
Fig. 3  Brief summary of immune regulatory networks of γδ T cells involved in the microenvironment of liver cancer.

The immune regulatory network of γδ T cells in liver cancer is extremely sophisticated and multivariant. Immune regulatory networks of γδ T cells are involved in the immune microenvironment of liver cancer through immune molecules, immune cells and nonimmune components. CD, cluster of differentiation; NK cell, natural-killer cell; MDSC, Myeloid-derived suppressor cell; Treg cell, T regulatory cell; CCR, C-C chemokine receptor; IL, interleukin; IFN-γ, interferon γ; TNF-α, tumor necrosis factor-α.

γδ T-cell-based immunotherapy in liver cancer

γδ T-cell-based immunotherapy in liver cancer is being vigorously developed and has achieved surprising results. According to current research results, there are three mainstream directions for γδ T-cell-based immunotherapy, namely, synergistic effects of other antibodies, chimeric antigen receptor-based γδ T cells, and γδ T-cell transplantation. The practical application of γδ T cell-centered immunotherapy in liver cancer is both promising and challenging with tremendous room for exploration. Studies of potential γδ T-cell-based immunotherapy in liver cancer is summarized in Table 1.70,120–127

Table 1

Studies of potential γδ T-cell-based immunotherapy in liver cancer

TreatmentTumor typeEffector cellsMechanismOutcomesReference
Zoledronic acidSK-HEP-1 and H22 cells–ZOL optimizes γδ T-cell-mediated immunotherapy and inhibits growth of HCC cellsInhibited tumor proliferation120
ZoledronateHepatocellular carcinoma and colorectal carcinoma with hepatic metastasesVγ9Vδ2 T cellsThe cytotoxic level of Vγ9Vδ2 T cells against freshly autologous tumor cells isolated from patients could be significantly increased by pretreating the tumor cells with zoledronateImproved cytotoxicity123
Zoledronate and IL-2Hepatocellular carcinomaγδ T cellsZoledronate with IL-2 may efficiently expand γδ T cells sourced from the peripheral blood of patients with HCCIncreased the quantity of the γδ T cells127
EpCAM-specific monoclonal antibodiesHepatoblastomaγδ T cellsTumor cell lysis by γδ T cells can be dramatically augmentedImproved cytotoxicity121
ChemotherapyMetastatic liver cancerVδ2+ T cellsVδ2+ T cells are coupled with impairments in quantity, cytotoxicity and production of TNF-α and IFN-γDecreased cytotoxicity122
Glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15Hepatocellular carcinomaCAR Vδ1 T cellsGPC-3.CAR/sIL-15 Vδ1 T cells displayed robust in vitro and vivo proliferation, cytokine production, cytotoxic activity and suppression of tumor growthDelayed tumour growth124
The expanded γδ T cells from healthy donorsLate-stage liver cancerVγ9Vδ2 T cellsThe expanded γδ T cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model, with the safety and efficacy in clinical trialImproved antitumor efficacy and prolonged survival time of patients70
The expanded γδ T cells from healthy donorsCholangiocarcinomaVγ9Vδ2 T cellAllogenic γδ T cell treatments positively regulated peripheral immune functions of the patient, depleted tumor activity, improved quality of life, and prolonged his life spanImproved antitumor efficacy125
Locoregional Therapy Combined with Adoptive Transfer of Allogeneic γδ T CellsHepatocellular Carcinoma and Intrahepatic Cholangiocarcinomaγδ T cellsThe novel combination of locoregional ablation with adoptive transfer of allogeneic γδ T cells was safe, and patients with HCC in the combined treatment group had a longer OS.Prolonged survival time of patients126

Synergistic effects of other antibodies

The cytotoxicity of γδ T cells in human liver sinuses depends on the signaling of phosphoantigens, NK receptors, and immune checkpoint molecules. Nitrogen-containing bisphosphonates have been widely used in tumor treatment, with outstanding therapeutic achievements.128–132 Similarly, in HCC, the addition of zoledronate markedly optimizes γδ T-cell-mediated immunotherapy and directly inhibits tumor proliferation.120,133 Moreover, the addition of EpCAM-specific monoclonal antibodies can prominently enhance the lysis effect of γδ T cells on hepatoblastoma.121 Another study also revealed a thought-provoking phenomenon in which chemotherapy accelerates the immune senescence and dysfunction of Vδ2 γδ T cells in patients with metastatic liver cancer.122 Therefore, the combination of γδ T cells and other drugs or antibodies is a double-edged sword that requires more clinical practice to provide more favorable evidence.

Chimeric antigen receptor (CAR) T-cell immunotherapy

CAR-T-cell immunotherapy is a precise and efficient tumor treatment method, while CAR-γδ T cells possess the advantages of both treatments, pushing tumor immunotherapy to a new level. This strategy has been applied in clinical practice in hematological tumors and has great potential in solid tumors.123,134–137 Vδ1 γδ T cells engineered with glypican-3-specific CAR and soluble IL-15 efficiently and robustly control tumor growth in HCC and exhibit strong tumor tissue aggregation.124 Although promising, some technical problems related to CAR-γδ T cells still need to be addressed, such as antigen recognition and design, gene delivery technology, and cell proliferation.

γδ T-cell transplantation.

As HCC progresses, the function of γδ T cells is lost, and the Vδ2 γδ T-cell population is heavily consumed.90 At the same time, the expression of immunosuppressive receptors in the Vδ1 γδ T-cell population is upregulated, and the antitumor ability of Vδ2 γδ T cells is enhanced.138 Therefore, allogeneic Vδ2 γδ T cells serve as a promising supplement in the treatment of liver cancer. In a study of Vγ9Vδ2 T-cell adoptive therapy, expanded cells also displayed robust antitumor efficacy against HCC and improved immune efficacy functions, including antitumor ability, proliferation, and differentiation.70 In corresponding clinical trials, the prolonged survival time of patients confirmed the safety and effectiveness of allogeneic Vγ9Vδ2 T-cell immunotherapy.70,125,128 Four clinical trials related to liver cancer have been registered so far (https://www.clinicaltrials.gov/ ID: NCT02425735, NCT03183219, NCT04518774, NCT05628545). In this clinical trial of advanced liver cancer (NCT03183219), of the 8 liver cancer patients, 7 survived for more than 10 months, and 3 survived for more than 30 months.70 Moreover, local regional therapy combined with allogeneic γδ T-cell adoptive transplantation is also very safe and effective in the treatment of advanced HCC and intrahepatic cholangiocarcinoma.126

For liver cancer patients, the optimization of γδ T-cell immunotherapy emphasizes individualization. The quality of γδ T-cell amplification is related to clinical and pathological characteristics such as tumor size, quantity, and serum AFP levels.127 During γδ T cell immunotherapy, the physiological and biochemical indicators of patients should be dynamically monitored to maximize the advantages of γδ T cell immunotherapy.127

Conclusions and future perspectives

An increasing number of studies have confirmed the unique properties of γδ T cells and their plasticity in the field of cancer research. Different subtypes of γδ T cells and their secreted cytokines have different protumor or antitumor effects. The enormous immune regulatory network formed around γδ T cells, including immune and nonimmune components in the microenvironment of liver cancer, regulates the differentiation and performance of γδ T cells and determines the ultimate occurrence and development of liver cancer. γδ T-cell-based immunotherapy has gradually become a highly promising treatment protocol for liver cancer, accompanied by opportunities and challenges. However, the exploration of γδ T cells in liver cancer is still incomplete, and more systematic and accurate explorations are still needed in many aspects. First, the heterogeneity of γδ T cells needs to be emphasized during research, as the functions of different subpopulations are completely different. Second, breakthroughs and innovations in technology and methods, such as the application of high-throughput technologies and the development of stable transfer models of γδ T cells, can broaden the horizons of γδ T cell research. Third, research on how to thoroughly induce the activation of γδ T cells in clinical applications and develop specific engineered γδ T cells targeting tumor antigens still requires in-depth explorations of tumor-related mechanisms. Fourth, combination strategies with other forms of treatment, such as surgery and targeted therapy, should also be the focus of future clinical investigation. Although research on γδ T cells is still in its infancy due to some technological limitations, γδ T cells, as attractive antitumor candidates, undoubtedly increase the understanding of liver cancer, and the application of γδ T cells in the field of liver cancer has great potential and a promising future.

Abbreviations

APCs: 

antigen-presenting cells

ADCC: 

antibody-dependent cell-mediated cytotoxicity

CAR-T cells: 

chimeric antigen receptor T cells

CCR: 

C-C chemokine receptor

CCL: 

C-C motif chemokine ligand

DCs: 

dendritic cells

HSCs: 

hepatic stellate cells

MDSCs: 

myeloid-derived suppressor cells

NKs: 

natural killer cells

NKRs: 

natural killer cell receptors

TME: 

tumor microenvironment

ZOL: 

zoledronate

Declarations

Acknowledgement

Thanks ‘HOME for Researchers’ and ‘Figdraw’ for the graphic assistance.

Funding

This study was supported partly by grants from National Natural Science Foundation (81972214, 82373348), Shanghai Natural Science Foundation (21140903500), the Natural Science Foundation of Chongqing (No. CSTB2022NSCQ-MSX0112); Science and Health Joint Research Project of Chongqing Municipality (2020GDRC013); Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0087).

Conflict of interest

RL has been an editorial board member of Journal of Clinical and Translational Hepatology since 2022. The other authors have no conflict of interests related to this publication

Authors’ contributions

Study concept and design (KLY, KJC, DF, RL), drafting of the manuscript (KJC, ML, YXD, YXY, MQK), critical revision of the manuscript for important intellectual content (KJC, ML, YXD, YXY, MQK), administrative or material support (KJC, DF, RL), and study supervision (KLY, KJC, DF, RL), critical funding (DF, RL). All authors have made a significant contribution to this study and have approved the final manuscript.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394-424 View Article PubMed/NCBI
  2. Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet 2022;400(10360):1345-1362 View Article PubMed/NCBI
  3. Donne R, Lujambio A. The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology 2023;77(5):1773-1796 View Article PubMed/NCBI
  4. Sas Z, Cendrowicz E, Weinhäuser I, Rygiel TP. Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options. Int J Mol Sci 2022;23(7):3778 View Article PubMed/NCBI
  5. Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol 2016;65(4):798-808 View Article PubMed/NCBI
  6. Lv Y, Wang Z, Yuan K. Role of Noncoding RNAs in the Tumor Immune Microenvironment of Hepatocellular Carcinoma. J Clin Transl Hepatol 2023;11(3):682-694 View Article PubMed/NCBI
  7. Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA. Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci 2009;1155:206-221 View Article PubMed/NCBI
  8. Villanueva A. Hepatocellular Carcinoma. N Engl J Med 2019;380(15):1450-1462 View Article PubMed/NCBI
  9. Colli LM, Machiela MJ, Zhang H, Myers TA, Jessop L, Delattre O, et al. Landscape of Combination Immunotherapy and Targeted Therapy to Improve Cancer Management. Cancer Res 2017;77(13):3666-3671 View Article PubMed/NCBI
  10. Zhou C, Weng J, Gao Y, Liu C, Zhu X, Zhou Q, et al. A Novel mRNA Signature Related to Immunity to Predict Survival and Immunotherapy Response in Hepatocellular Carcinoma. J Clin Transl Hepatol 2022;10(5):925-938 View Article PubMed/NCBI
  11. Duan Y, Zhang H, Tan T, Ye W, Yin K, Yu Y, et al. The immune response of hepatocellular carcinoma after locoregional and systemic therapies: The available combination option for immunotherapy. Biosci Trends 2023 View Article PubMed/NCBI
  12. Kumar N, Khakoo SI. Hepatocellular carcinoma: Prospects for natural killer cell immunotherapy. HLA 2018;92(1):3-11 View Article PubMed/NCBI
  13. Chu J, Gao F, Yan M, Zhao S, Yan Z, Shi B, et al. Natural killer cells: a promising immunotherapy for cancer. J Transl Med 2022;20(1):240 View Article PubMed/NCBI
  14. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018;359(6382):1361-1365 View Article PubMed/NCBI
  15. Titov A, Zmievskaya E, Ganeeva I, Valiullina A, Petukhov A, Rakhmatullina A, et al. Adoptive Immunotherapy beyond CAR T-Cells. Cancers (Basel) 2021;13(4):743 View Article PubMed/NCBI
  16. Brenner MB, McLean J, Dialynas DP, Strominger JL, Smith JA, Owen FL, et al. Identification of a putative second T-cell receptor. Nature 1986;322(6075):145-149 View Article PubMed/NCBI
  17. Groh V, Porcelli S, Fabbi M, Lanier LL, Picker LJ, Anderson T, et al. Human lymphocytes bearing T cell receptor gamma/delta are phenotypically diverse and evenly distributed throughout the lymphoid system. J Exp Med 1989;169(4):1277-1294 View Article PubMed/NCBI
  18. Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2002;2(5):336-345 View Article PubMed/NCBI
  19. Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006;43(2 Suppl 1):S54-S62 View Article PubMed/NCBI
  20. Hunter S, Willcox CR, Davey MS, Kasatskaya SA, Jeffery HC, Chudakov DM, et al. Human liver infiltrating γδ T cells are composed of clonally expanded circulating and tissue-resident populations. J Hepatol 2018;69(3):654-665 View Article PubMed/NCBI
  21. Fiala GJ, Gomes AQ, Silva-Santos B. From thymus to periphery: Molecular basis of effector γδ-T cell differentiation. Immunol Rev 2020;298(1):47-60 View Article PubMed/NCBI
  22. Michie AM, Zúñiga-Pflücker JC. Regulation of thymocyte differentiation: pre-TCR signals and beta-selection. Semin Immunol 2002;14(5):311-323 View Article PubMed/NCBI
  23. Ferreira LM. Gammadelta T cells: innately adaptive immune cells?. Int Rev Immunol 2013;32(3):223-248 View Article PubMed/NCBI
  24. Pont F, Familiades J, Déjean S, Fruchon S, Cendron D, Poupot M, et al. The gene expression profile of phosphoantigen-specific human γδ T lymphocytes is a blend of αβ T-cell and NK-cell signatures. Eur J Immunol 2012;42(1):228-240 View Article PubMed/NCBI
  25. Roden AC, Morice WG, Hanson CA. Immunophenotypic attributes of benign peripheral blood gammadelta T cells and conditions associated with their increase. Arch Pathol Lab Med 2008;132(11):1774-1780 View Article PubMed/NCBI
  26. Nicolas L, Monneret G, Debard AL, Blesius A, Gutowski MC, Salles G, et al. Human gammadelta T cells express a higher TCR/CD3 complex density than alphabeta T cells. Clin Immunol 2001;98(3):358-363 View Article PubMed/NCBI
  27. Willcox CR, Mohammed F, Willcox BE. The distinct MHC-unrestricted immunobiology of innate-like and adaptive-like human γδ T cell subsets-Nature’s CAR-T cells. Immunol Rev 2020;298(1):25-46 View Article PubMed/NCBI
  28. Melandri D, Zlatareva I, Chaleil RAG, Dart RJ, Chancellor A, Nussbaumer O, et al. The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness. Nat Immunol 2018;19(12):1352-1365 View Article PubMed/NCBI
  29. Kazen AR, Adams EJ. Evolution of the V, D, and J gene segments used in the primate gammadelta T-cell receptor reveals a dichotomy of conservation and diversity. Proc Natl Acad Sci U S A 2011;108(29):E332-E340 View Article PubMed/NCBI
  30. Maeurer MJ, Martin D, Walter W, Liu K, Zitvogel L, Halusczcak K, et al. Human intestinal Vdelta1+ lymphocytes recognize tumor cells of epithelial origin. J Exp Med 1996;183(4):1681-1696 View Article PubMed/NCBI
  31. Chowers Y, Holtmeier W, Harwood J, Morzycka-Wroblewska E, Kagnoff MF. The V delta 1 T cell receptor repertoire in human small intestine and colon. J Exp Med 1994;180(1):183-190 View Article PubMed/NCBI
  32. Pauza CD, Cairo C. Evolution and function of the TCR Vgamma9 chain repertoire: It’s good to be public. Cell Immunol 2015;296(1):22-30 View Article PubMed/NCBI
  33. Mangan BA, Dunne MR, O’Reilly VP, Dunne PJ, Exley MA, O’Shea D, et al. Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human Vδ3 T cells. J Immunol 2013;191(1):30-34 View Article PubMed/NCBI
  34. Zhao Y, Niu C, Cui J. Gamma-delta (γδ) T cells: friend or foe in cancer development?. J Transl Med 2018;16(1):3 View Article PubMed/NCBI
  35. Davey MS, Willcox CR, Joyce SP, Ladell K, Kasatskaya SA, McLaren JE, et al. Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance. Nat Commun 2017;8:14760 View Article PubMed/NCBI
  36. Sanz M, Mann BT, Ryan PL, Bosque A, Pennington DJ, Hackstein H, et al. Deep characterization of human γδ T cell subsets defines shared and lineage-specific traits. Front Immunol 2023;14:1148988 View Article PubMed/NCBI
  37. Meraviglia S, Lo Presti E, Tosolini M, La Mendola C, Orlando V, Todaro M, et al. Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer. Oncoimmunology 2017;6(10):e1347742 View Article PubMed/NCBI
  38. Wu Y, Biswas D, Usaite I, Angelova M, Boeing S, Karasaki T, et al. A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer. Nat Cancer 2022;3(6):696-709 View Article PubMed/NCBI
  39. Tanaka Y, Morita CT, Tanaka Y, Nieves E, Brenner MB, Bloom BR. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 1995;375(6527):155-158 View Article PubMed/NCBI
  40. Hintz M, Reichenberg A, Altincicek B, Bahr U, Gschwind RM, Kollas AK, et al. Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli. FEBS Lett 2001;509(2):317-322 View Article PubMed/NCBI
  41. Sandstrom A, Peigné CM, Léger A, Crooks JE, Konczak F, Gesnel MC, et al. The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells. Immunity 2014;40(4):490-500 View Article PubMed/NCBI
  42. Payne KK, Mine JA, Biswas S, Chaurio RA, Perales-Puchalt A, Anadon CM, et al. BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells. Science 2020;369(6506):942-949 View Article PubMed/NCBI
  43. Cano CE, Pasero C, De Gassart A, Kerneur C, Gabriac M, Fullana M, et al. BTN2A1, an immune checkpoint targeting Vγ9Vδ2 T cell cytotoxicity against malignant cells. Cell Rep 2021;36(2):109359 View Article PubMed/NCBI
  44. Simões AE, Di Lorenzo B, Silva-Santos B. Molecular Determinants of Target Cell Recognition by Human γδ T Cells. Front Immunol 2018;9:929 View Article PubMed/NCBI
  45. Silva-Santos B, Strid J. Working in “NK Mode”: Natural Killer Group 2 Member D and Natural Cytotoxicity Receptors in Stress-Surveillance by γδ T Cells. Front Immunol 2018;9:851 View Article PubMed/NCBI
  46. Xi X, Guo Y, Zhu M, Qiu F, Lei F, Li G, et al. Identification of new potential antigen recognized by γδT cells in hepatocellular carcinoma. Cancer Immunol Immunother 2021;70(7):1917-1927 View Article PubMed/NCBI
  47. Hoh A, Dewerth A, Vogt F, Wenz J, Baeuerle PA, Warmann SW, et al. The activity of γδ T cells against paediatric liver tumour cells and spheroids in cell culture. Liver Int 2013;33(1):127-136 View Article PubMed/NCBI
  48. Ren H, Li W, Liu X, Zhao N. γδ T cells: The potential role in liver disease and implications for cancer immunotherapy. J Leukoc Biol 2022;112(6):1663-1668 View Article PubMed/NCBI
  49. Jiang H, Yang Z, Song Z, Green M, Song H, Shao Q. γδ T cells in hepatocellular carcinoma patients present cytotoxic activity but are reduced in potency due to IL-2 and IL-21 pathways. Int Immunopharmacol 2019;70:167-173 View Article PubMed/NCBI
  50. Liu B, He X, Wang Y, Huang JW, Zheng YB, Li Y, et al. Bibliometric Analysis of γδ T Cells as Immune Regulators in Cancer Prognosis. Front Immunol 2022;13:874640 View Article PubMed/NCBI
  51. Li T, Zhou Y, Sun X, Bian Y, Wang K, Guo Q, et al. Interleukin-2 maintains the survival of interleukin-17+ gamma/delta T cells in inflammation and autoimmune diseases. Int Immunopharmacol 2020;86:106721 View Article PubMed/NCBI
  52. Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ. Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Front Immunol 2018;9:847 View Article PubMed/NCBI
  53. Cheon H, Wang Y, Wightman SM, Jackson MW, Stark GR. How cancer cells make and respond to interferon-I. Trends Cancer 2023;9(1):83-92 View Article PubMed/NCBI
  54. Lança T, Costa MF, Gonçalves-Sousa N, Rei M, Grosso AR, Penido C, et al. Protective role of the inflammatory CCR2/CCL2 chemokine pathway through recruitment of type 1 cytotoxic γδ T lymphocytes to tumor beds. J Immunol 2013;190(12):6673-6680 View Article PubMed/NCBI
  55. Penido C, Costa MF, Souza MC, Costa KA, Candéa AL, Benjamim CF, et al. Involvement of CC chemokines in gammadelta T lymphocyte trafficking during allergic inflammation: the role of CCL2/CCR2 pathway. Int Immunol 2008;20(1):129-139 View Article PubMed/NCBI
  56. Wunderlich CM, Ackermann PJ, Ostermann AL, Adams-Quack P, Vogt MC, Tran ML, et al. Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment. Nat Commun 2018;9(1):1646 View Article PubMed/NCBI
  57. Reinhardt A, Ravens S, Fleige H, Haas JD, Oberdörfer L, Łyszkiewicz M, et al. CCR7-mediated migration in the thymus controls γδ T-cell development. Eur J Immunol 2014;44(5):1320-1329 View Article PubMed/NCBI
  58. Moser B, Brandes M. Gammadelta T cells: an alternative type of professional APC. Trends Immunol 2006;27(3):112-118 View Article PubMed/NCBI
  59. Collins C, Wolfe J, Roessner K, Shi C, Sigal LH, Budd RC. Lyme arthritis synovial gammadelta T cells instruct dendritic cells via fas ligand. J Immunol 2005;175(9):5656-5665 View Article PubMed/NCBI
  60. Zhu X, Zeng Z, Qiu D, Chen J. Vγ9Vδ2 T cells inhibit immature dendritic cell transdifferentiation into osteoclasts through downregulation of RANK, c-Fos and ATP6V0D2. Int J Mol Med 2018;42(4):2071-2079 View Article PubMed/NCBI
  61. Meuter S, Eberl M, Moser B. Prolonged antigen survival and cytosolic export in cross-presenting human gammadelta T cells. Proc Natl Acad Sci U S A 2010;107(19):8730-8735 View Article PubMed/NCBI
  62. Daley D, Zambirinis CP, Seifert L, Akkad N, Mohan N, Werba G, et al. γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation. Cell 2016;166(6):1485-1499.e15 View Article PubMed/NCBI
  63. Rampoldi F, Ullrich L, Prinz I. Revisiting the Interaction of γδ T-Cells and B-Cells. Cells 2020;9(3):743 View Article PubMed/NCBI
  64. Petrasca A, Melo AM, Breen EP, Doherty DG. Human Vδ3+ γδ T cells induce maturation and IgM secretion by B cells. Immunol Lett 2018;196:126-134 View Article PubMed/NCBI
  65. Mathews JA, Kasahara DI, Ribeiro L, Wurmbrand AP, Ninin FM, Shore SA. γδ T Cells Are Required for M2 Macrophage Polarization and Resolution of Ozone-Induced Pulmonary Inflammation in Mice. PLoS One 2015;10(7):e0131236 View Article PubMed/NCBI
  66. Nguyen CT, Furuya H, Das D, Marusina AI, Merleev AA, Ravindran R, et al. Peripheral γδ T Cells Regulate Neutrophil Expansion and Recruitment in Experimental Psoriatic Arthritis. Arthritis Rheumatol 2022;74(9):1524-1534 View Article PubMed/NCBI
  67. Bouchareychas L, Grössinger EM, Kang M, Adamopoulos IE. γδTCR regulates production of interleukin-27 by neutrophils and attenuates inflammatory arthritis. Sci Rep 2018;8(1):7590 View Article PubMed/NCBI
  68. Al Mogrampi S, Boumpoureka C, Afaloniati H, Lagou M, Angelopoulou K, Anestakis D, et al. Inhibition of γδ-TcR or IL17a Reduces T-Cell and Neutrophil Infiltration after Ischemia/Reperfusion Injury in Mouse Liver. J Clin Med 2023;12(5):1751 View Article PubMed/NCBI
  69. Zakeri N, Hall A, Swadling L, Pallett LJ, Schmidt NM, Diniz MO, et al. Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma. Nat Commun 2022;13(1):1372 View Article PubMed/NCBI
  70. Xu Y, Xiang Z, Alnaggar M, Kouakanou L, Li J, He J, et al. Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer. Cell Mol Immunol 2021;18(2):427-439 View Article PubMed/NCBI
  71. Kang Y, Han M, Kim M, Hwang HJ, Ahn BC, Tak E, et al. Cytotoxicity of Human Hepatic Intrasinusoidal Gamma/Delta T Cells Depends on Phospho-antigen and NK Receptor Signaling. Anticancer Res 2023;43(1):63-73 View Article PubMed/NCBI
  72. Kamimura H, Yamagiwa S, Tsuchiya A, Takamura M, Matsuda Y, Ohkoshi S, et al. Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J Hepatol 2012;56(2):381-388 View Article PubMed/NCBI
  73. Kong Y, Cao W, Xi X, Ma C, Cui L, He W. The NKG2D ligand ULBP4 binds to TCRgamma9/delta2 and induces cytotoxicity to tumor cells through both TCRgammadelta and NKG2D. Blood 2009;114(2):310-317 View Article PubMed/NCBI
  74. Lança T, Correia DV, Moita CF, Raquel H, Neves-Costa A, Ferreira C, et al. The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to gammadelta T-cell cytotoxicity. Blood 2010;115(12):2407-2411 View Article PubMed/NCBI
  75. Cadoux M, Caruso S, Pham S, Gougelet A, Pophillat C, Riou R, et al. Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness. J Hepatol 2021;74(6):1386-1397 View Article PubMed/NCBI
  76. Rincon-Orozco B, Kunzmann V, Wrobel P, Kabelitz D, Steinle A, Herrmann T. Activation of V gamma 9V delta 2 T cells by NKG2D. J Immunol 2005;175(4):2144-2151 View Article PubMed/NCBI
  77. Li P, Du Q, Cao Z, Guo Z, Evankovich J, Yan W, et al. Interferon-γ induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon-regulatory factor-1 (IRF-1). Cancer Lett 2012;314(2):213-222 View Article PubMed/NCBI
  78. Jang MK, Kim HS, Chung YH. Clinical aspects of tumor necrosis factor-α signaling in hepatocellular carcinoma. Curr Pharm Des 2014;20(17):2799-2808 View Article PubMed/NCBI
  79. Toutirais O, Cabillic F, Le Friec G, Salot S, Loyer P, Le Gallo M, et al. DNAX accessory molecule-1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vgamma9Vdelta2 T cells. Eur J Immunol 2009;39(5):1361-1368 View Article PubMed/NCBI
  80. Bruni E, Cimino MM, Donadon M, Carriero R, Terzoli S, Piazza R, et al. Intrahepatic CD69(+)Vδ1 T cells re-circulate in the blood of patients with metastatic colorectal cancer and limit tumor progression. J Immunother Cancer 2022;10(7):e004579 View Article PubMed/NCBI
  81. Bertaina A, Zorzoli A, Petretto A, Barbarito G, Inglese E, Merli P, et al. Zoledronic acid boosts γδ T-cell activity in children receiving αβ(+) T and CD19(+) cell-depleted grafts from an HLA-haplo-identical donor. Oncoimmunology 2017;6(2):e1216291 View Article PubMed/NCBI
  82. Hodgins NO, Al-Jamal WT, Wang JT, Parente-Pereira AC, Liu M, Maher J, et al. In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice. J Control Release 2016;241:229-241 View Article PubMed/NCBI
  83. Qian P, Zhang YW, Zhou ZH, Liu JQ, Yue SY, Guo XL, et al. Artesunate enhances γδ T-cell-mediated antitumor activity through augmenting γδ T-cell function and reversing immune escape of HepG2 cells. Immunopharmacol Immunotoxicol 2018;40(2):107-116 View Article PubMed/NCBI
  84. Patil RS, Shah SU, Shrikhande SV, Goel M, Dikshit RP, Chiplunkar SV. IL17 producing γδT cells induce angiogenesis and are associated with poor survival in gallbladder cancer patients. Int J Cancer 2016;139(4):869-881 View Article PubMed/NCBI
  85. Gu FM, Li QL, Gao Q, Jiang JH, Zhu K, Huang XY, et al. IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer 2011;10:150 View Article PubMed/NCBI
  86. Wakita D, Sumida K, Iwakura Y, Nishikawa H, Ohkuri T, Chamoto K, et al. Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis. Eur J Immunol 2010;40(7):1927-1937 View Article PubMed/NCBI
  87. Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 2015;522(7556):345-348 View Article PubMed/NCBI
  88. Edwards SC, Hedley A, Hoevenaar WHM, Wiesheu R, Glauner T, Kilbey A, et al. PD-1 and TIM-3 differentially regulate subsets of mouse IL-17A-producing γδ T cells. J Exp Med 2023;220(2):e20211431 View Article PubMed/NCBI
  89. Barsch M, Salié H, Schlaak AE, Zhang Z, Hess M, Mayer LS, et al. T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma. J Hepatol 2022;77(2):397-409 View Article PubMed/NCBI
  90. He W, Hu Y, Chen D, Li Y, Ye D, Zhao Q, et al. Hepatocellular carcinoma-infiltrating γδ T cells are functionally defected and allogenic Vδ2(+) γδ T cell can be a promising complement. Clin Transl Med 2022;12(4):e800 View Article PubMed/NCBI
  91. Ma S, Cheng Q, Cai Y, Gong H, Wu Y, Yu X, et al. IL-17A produced by γδ T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res 2014;74(7):1969-1982 View Article PubMed/NCBI
  92. Kühl AA, Pawlowski NN, Grollich K, Blessenohl M, Westermann J, Zeitz M, et al. Human peripheral gammadelta T cells possess regulatory potential. Immunology 2009;128(4):580-588 View Article PubMed/NCBI
  93. Lafont V, Sanchez F, Laprevotte E, Michaud HA, Gros L, Eliaou JF, et al. Plasticity of γδ T Cells: Impact on the Anti-Tumor Response. Front Immunol 2014;5:622 View Article PubMed/NCBI
  94. Sabbione F, Gabelloni ML, Ernst G, Gori MS, Salamone G, Oleastro M, et al. Neutrophils suppress γδ T-cell function. Eur J Immunol 2014;44(3):819-830 View Article PubMed/NCBI
  95. Li L, Cao B, Liang X, Lu S, Luo H, Wang Z, et al. Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes. Oncogene 2019;38(15):2830-2843 View Article PubMed/NCBI
  96. Mamedov MR, Vedova S, Freimer JW, Sahu AD, Ramesh A, Arce MM, et al. CRISPR screens decode cancer cell pathways that trigger γδ T cell detection. Nature 2023;621(7977):188-195 View Article PubMed/NCBI
  97. Torres-Hernandez A, Wang W, Nikiforov Y, Tejada K, Torres L, Kalabin A, et al. γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming. Hepatology 2020;71(2):477-494 View Article PubMed/NCBI
  98. Hu Y, Chen D, Hong M, Liu J, Li Y, Hao J, et al. Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance. Front Immunol 2022;13:845974 View Article PubMed/NCBI
  99. Sugai S, Yoshikawa T, Iwama T, Tsuchiya N, Ueda N, Fujinami N, et al. Hepatocellular carcinoma cell sensitivity to Vγ9Vδ2 T lymphocyte-mediated killing is increased by zoledronate. Int J Oncol 2016;48(5):1794-1804 View Article PubMed/NCBI
  100. Chen Z, Zheng Z, Feng L, Huo Z, Huang L, Fu M, et al. Overexpression of miR-382 Sensitizes Hepatocellular Carcinoma Cells to γδ T Cells by Inhibiting the Expression of c-FLIP. Mol Ther Oncolytics 2020;18:467-475 View Article PubMed/NCBI
  101. Seo W, Eun HS, Kim SY, Yi HS, Lee YS, Park SH, et al. Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis. Hepatology 2016;64(2):616-631 View Article PubMed/NCBI
  102. Zhou BY, Gong JH, Cai XY, Wang JX, Luo F, Jiang N, et al. An imbalance between stellate cells and γδT cells contributes to hepatocellular carcinoma aggressiveness and recurrence. Hepatol Int 2019;13(5):631-640 View Article PubMed/NCBI
  103. Brandes M, Willimann K, Moser B. Professional antigen-presentation function by human gammadelta T Cells. Science 2005;309(5732):264-268 View Article PubMed/NCBI
  104. Muto M, Baghdadi M, Maekawa R, Wada H, Seino K. Myeloid molecular characteristics of human γδ T cells support their acquisition of tumor antigen-presenting capacity. Cancer Immunol Immunother 2015;64(8):941-949 View Article PubMed/NCBI
  105. Sacchi A, Tumino N, Sabatini A, Cimini E, Casetti R, Bordoni V, et al. Myeloid-Derived Suppressor Cells Specifically Suppress IFN-γ Production and Antitumor Cytotoxic Activity of Vδ2 T Cells. Front Immunol 2018;9:1271 View Article PubMed/NCBI
  106. Yi Y, He HW, Wang JX, Cai XY, Li YW, Zhou J, et al. The functional impairment of HCC-infiltrating γδ T cells, partially mediated by regulatory T cells in a TGFβ- and IL-10-dependent manner. J Hepatol 2013;58(5):977-983 View Article PubMed/NCBI
  107. Ye J, Ma C, Hsueh EC, Eickhoff CS, Zhang Y, Varvares MA, et al. Tumor-derived γδ regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence. J Immunol 2013;190(5):2403-2414 View Article PubMed/NCBI
  108. Peters C, Kabelitz D, Wesch D. Regulatory functions of γδ T cells. Cell Mol Life Sci 2018;75(12):2125-2135 View Article PubMed/NCBI
  109. Zhao N, Dang H, Ma L, Martin SP, Forgues M, Ylaya K, et al. Intratumoral γδ T-Cell Infiltrates, Chemokine (C-C Motif) Ligand 4/Chemokine (C-C Motif) Ligand 5 Protein Expression and Survival in Patients With Hepatocellular Carcinoma. Hepatology 2021;73(3):1045-1060 View Article PubMed/NCBI
  110. Glatzel A, Wesch D, Schiemann F, Brandt E, Janssen O, Kabelitz D. Patterns of chemokine receptor expression on peripheral blood gamma delta T lymphocytes: strong expression of CCR5 is a selective feature of V delta 2/V gamma 9 gamma delta T cells. J Immunol 2002;168(10):4920-4929 View Article PubMed/NCBI
  111. Li X, Yao W, Yuan Y, Chen P, Li B, Li J, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 2017;66(1):157-167 View Article PubMed/NCBI
  112. Ajuebor MN, Jin Y, Gremillion GL, Strieter RM, Chen Q, Adegboyega PA. GammadeltaT cells initiate acute inflammation and injury in adenovirus-infected liver via cytokine-chemokine cross talk. J Virol 2008;82(19):9564-9576 View Article PubMed/NCBI
  113. Russo RC, Savino B, Mirolo M, Buracchi C, Germano G, Anselmo A, et al. The atypical chemokine receptor ACKR2 drives pulmonary fibrosis by tuning influx of CCR2+ and CCR5+ IFNγ-producing γδT cells in mice. Am J Physiol Lung Cell Mol Physiol 2018;314(6):L1010-L1025 View Article PubMed/NCBI
  114. Hammerich L, Bangen JM, Govaere O, Zimmermann HW, Gassler N, Huss S, et al. Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis. Hepatology 2014;59(2):630-642 View Article PubMed/NCBI
  115. Hao J, Dong S, Xia S, He W, Jia H, Zhang S, et al. Regulatory role of Vγ1 γδ T cells in tumor immunity through IL-4 production. J Immunol 2011;187(10):4979-4986 View Article PubMed/NCBI
  116. Ren H, Liu X, Xu Q, Li W, Zhao N. Interleukin-35 expression promotes hepatocellular carcinogenesis by inducing γδ T-cell exhaustion. Genomics 2023;115(3):110639 View Article PubMed/NCBI
  117. Hoeres T, Holzmann E, Smetak M, Birkmann J, Wilhelm M. PD-1 signaling modulates interferon-γ production by Gamma Delta (γδ) T-Cells in response to leukemia. Oncoimmunology 2019;8(3):1550618 View Article PubMed/NCBI
  118. Sheng Y, Chen K, Jiang W, Wu Z, Zhang W, Jing H, et al. PD-1 restrains IL-17A production from γδ T cells to modulate acute radiation-induced lung injury. Transl Lung Cancer Res 2021;10(2):685-698 View Article PubMed/NCBI
  119. Zheng J, Qiu D, Jiang X, Zhao Y, Zhao H, Wu X, et al. Increased PD-1(+)Foxp3(+) γδ T cells associate with poor overall survival for patients with acute myeloid leukemia. Front Oncol 2022;12:1007565 View Article PubMed/NCBI
  120. Liu Q, Tao YH, Bai RZ, Chang SJ, Hua D. Zoledronic acid inhibits growth of hepatocellular carcinoma cells in vitro and in vivo. Chin Med J (Engl) 2013;126(8):1486-1490 View Article PubMed/NCBI
  121. Armeanu-Ebinger S, Hoh A, Wenz J, Fuchs J. Targeting EpCAM (CD326) for immunotherapy in hepatoblastoma. Oncoimmunology 2013;2(1):e22620 View Article PubMed/NCBI
  122. Bruni E, Cazzetta V, Donadon M, Cimino M, Torzilli G, Spata G, et al. Chemotherapy accelerates immune-senescence and functional impairments of Vδ2(pos) T cells in elderly patients affected by liver metastatic colorectal cancer. J Immunother Cancer 2019;7(1):347 View Article PubMed/NCBI
  123. Capsomidis A, Benthall G, Van Acker HH, Fisher J, Kramer AM, Abeln Z, et al. Chimeric Antigen Receptor-Engineered Human Gamma Delta T Cells: Enhanced Cytotoxicity with Retention of Cross Presentation. Mol Ther 2018;26(2):354-365 View Article PubMed/NCBI
  124. Makkouk A, Yang XC, Barca T, Lucas A, Turkoz M, Wong JTS, et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma. J Immunother Cancer 2021;9(12):e003441 View Article PubMed/NCBI
  125. Varon S, Skaper SD, Barbin G, Selak I, Manthorpe M. Low molecular weight agents support survival of cultured neurons from the central nervous system. J Neurosci 1984;4(3):654-658 View Article PubMed/NCBI
  126. Zhang T, Chen J, Niu L, Liu Y, Ye G, Jiang M, et al. Clinical Safety and Efficacy of Locoregional Therapy Combined with Adoptive Transfer of Allogeneic γδ T Cells for Advanced Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. J Vasc Interv Radiol 2022;33(1):19-27.e3 View Article PubMed/NCBI
  127. Tian W, Ma J, Shi R, Ren C, He J, Zhao H. γδ T cell-mediated individualized immunotherapy for hepatocellular carcinoma considering clinicopathological characteristics and immunosuppressive factors. Oncol Lett 2018;15(4):5433-5442 View Article PubMed/NCBI
  128. Cabillic F, Toutirais O, Lavoué V, de La Pintière CT, Daniel P, Rioux-Leclerc N, et al. Aminobisphosphonate-pretreated dendritic cells trigger successful Vgamma9Vdelta2 T cell amplification for immunotherapy in advanced cancer patients. Cancer Immunol Immunother 2010;59(11):1611-1619 View Article PubMed/NCBI
  129. Fusco V, Campisi G, Bedogni A. One changing and challenging scenario: the treatment of cancer patients with bone metastases by bisphosphonates and denosumab, the cost-benefit evaluation of different options, and the risk of medication-related osteonecrosis of the jaw (MRONJ). Support Care Cancer 2022;30(9):7047-7051 View Article PubMed/NCBI
  130. Tuesley KM, Webb PM, Protani MM, Spilsbury K, Pearson SA, Coory MD, et al. Nitrogen-based Bisphosphonate Use and Ovarian Cancer Risk in Women Aged 50 Years and Older. J Natl Cancer Inst 2022;114(6):878-884 View Article PubMed/NCBI
  131. Wei Z, Pan B, Jia D, Yu Y. Long-term safety and efficacy of bisphosphonate therapy in advanced lung cancer with bone metastasis. Future Oncol 2022;18(18):2257-2267 View Article PubMed/NCBI
  132. Sorscher S. Duration and Dose of Adjuvant Zoledronic Acid for Treatment of Early Breast Cancer. JAMA Oncol 2022;8(1):171 View Article PubMed/NCBI
  133. Bouet-Toussaint F, Cabillic F, Toutirais O, Le Gallo M, Thomas de la Pintière C, Daniel P, et al. Vgamma9Vdelta2 T cell-mediated recognition of human solid tumors. Potential for immunotherapy of hepatocellular and colorectal carcinomas. Cancer Immunol Immunother 2008;57(4):531-539 View Article PubMed/NCBI
  134. Ferry GM, Agbuduwe C, Forrester M, Dunlop S, Chester K, Fisher J, et al. A Simple and Robust Single-Step Method for CAR-Vδ1 γδT Cell Expansion and Transduction for Cancer Immunotherapy. Front Immunol 2022;13:863155 View Article PubMed/NCBI
  135. Rozenbaum M, Meir A, Aharony Y, Itzhaki O, Schachter J, Bank I, et al. Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia. Front Immunol 2020;11:1347 View Article PubMed/NCBI
  136. Ganapathy T, Radhakrishnan R, Sakshi S, Martin S. CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green?. Cancer Immunol Immunother 2023;72(2):277-286 View Article PubMed/NCBI
  137. Nishimoto KP, Barca T, Azameera A, Makkouk A, Romero JM, Bai L, et al. Allogeneic CD20-targeted γδ T cells exhibit innate and adaptive antitumor activities in preclinical B-cell lymphoma models. Clin Transl Immunology 2022;11(2):e1373 View Article PubMed/NCBI
  138. Sun R, Li J, Lin X, Yang Y, Liu B, Lan T, et al. Peripheral immune characteristics of hepatitis B virus-related hepatocellular carcinoma. Front Immunol 2023;14:1079495 View Article PubMed/NCBI

Copyright © 2022 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Download PDF

Metrics

Article accesses:
4508

Citation

Order Reprints
  • Copyright © 2022 JCTH. All Rights Reserved.
  • Published by Xia & He Publishing Inc.
  • Address: 14090 Southwest Freeway, Suite 300, Sugar Land, Texas 77478, USA
  • Email: service@xiahepublishing.com