Trends in Immunology
ReviewThe Ambiguous Role of γδ T Lymphocytes in Antitumor Immunity
Section snippets
Recognition of Tumor Cells by γδ T Cells
T cells expressing a heterodimeric γδ T cell receptor (TCR, see Glossary) are a numerically small subset of CD3+ T lymphocytes in peripheral blood, although they are present at increased frequency in mucosal tissues and the skin. Conventional αβ T cells express a TCR that is generated from a large germline pool of variable α (Vα) and Vβ gene segments, and accordingly can recognize a large variety of peptides in the context of MHC molecules [1]. By contrast, only a few Vγ and Vδ genes are
γδ T Cells Kill Tumor Cells In Vitro and In Vivo
A broad range of tumor cells, including prostate cancer, melanoma, metastatic renal carcinoma, breast and ovarian cancer, colon carcinoma, hepatocellular carcinoma, lung cancer, and myeloma, have been found to be sensitive to killing by human γδ T cells ([29] for review). In the case of Vδ2 T cells, recognition of transformed cells is usually linked to augmented production of IPP which is further increased by zoledronic acid or a related n-BP 27, 30, 31, 32, 33, 34. Vδ1 T cells, by contrast, are
Intratumoral γδ T Cells May Promote Tumorigenesis
In accordance with their pronounced antitumor efficacy, the proportion of γδ T cells among tumor-infiltrating lymphocytes (TILs) was found to be the best positive predictive parameter across a multitude of human tumor entities [72]. Surprisingly, however, several recent studies indicate that tumor-infiltrating γδ T cells might also exert opposite effects, in other words they might promote tumorigenesis by various mechanisms (Figure 3). As an example, Vδ1 γδ T cells found at increased numbers
How To Enhance Antitumor and Minimize Protumorigenic Activities of γδ T Cells
As discussed, γδ T cells are promising candidates for cellular immunotherapy but may also support tumorigenesis. It is thus mandatory to design strategies to circumvent the inhibitory activities while enhancing the antitumor efficacy of γδ T cells. A schematic summary of possible approaches is depicted in Figure 4. While zoledronic acid (and in some instances pAgs such as BrHPP) plus IL-2 have been traditionally used for in vivo activation and large-scale in vitro expansion of Vδ2 T cells, an
Concluding Remarks
γδ T cells have fascinating perspectives for clinical application in cell-based immunotherapy. The recent burst of translational interest in γδ T cells is also reflected by several new biotech companies with a focus on bringing γδ T cells to clinic application (GammaDelta Therapeutics, Incysus, Gadeta, PhosphoGam, Lymphocyte Activation Technologies). In view of the contrasting antitumor and protumorigenic effects discussed here, several issues need to be addressed en route to optimizing
Acknowledgments
Work from our laboratory was supported by the Deutsche Forschungsgemeinschaft (grants Ka502/16-1, EXC 306).
Glossary
- Aminobisphosphonates (n-BPs)
- drugs in clinical use for the treatment of bone diseases. n-BPs inhibit an enzyme in the mevalonate pathway, leading to increased upstream accumulation of the γδ T cell-stimulating pAg IPP.
- Bispecific antibody, tribody
- recombinant antibody constructs [e.g., two single-chain fragment variable (scFv) or two antigen-specific scFv fused to a Fab fragmnt (tribody)].
- Butyrophilin 3A (BTN3A)
- butyrophilins comprise a large family of proteins with different roles in the immune
References (96)
Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells
Immunity
(1995)Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset
Blood
(2012)The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells
Immunity
(2014)RhoB mediates phosphoantigen recognition by Vγ9Vδ2 T cell receptor
Cell Rep.
(2016)Bisphosphonates for cancer treatment: mechanisms of action and lessons from clinical trials
Pharmacol. Ther.
(2016)Tumor recognition following Vγ9Vδ2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I
Immunity
(2005)- et al.
Cytotoxic and regulatory properties of circulating Vδ1+ γδ T cells: a new player on the cell therapy field?
Mol. Ther.
(2014) Zoledronate facilitates large-scale ex vivo expansion of functional γδ T cells from cancer patients for use in adoptive immunotherapy
Cytotherapy
(2008)Adoptive transfer of ex vivo expanded Vγ9Vδ2 T cells in combination with zoledronic acid inhibits cancer growth and limits osteolysis in a murine model of osteolytic breast cancer
Cancer Lett.
(2017)Targeted activation of human Vγ9Vδ2-T cells controls Epstein–Barr virus-induced B cell lymphoproliferative disease
Cancer Cell
(2014)
Zoledronate-activated Vγ9 γδ T cell-based immunotherapy is feasible and restores the impairment of γδ T cells in patients with solid tumors
Cytotherapy
Harnessing γδ T cells in anticancer immunotherapy
Trends Immunol.
CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date
Blood
Tumor-infiltrating γδ T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway
Immunity
γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer
Immunity
αβ TCR-mediated recognition: relevance to tumor-antigen discovery and cancer immunotherapy
Cancer Immunol. Res.
Identification of the complete expressed human TCR Vγ repertoire by flow cytometry
Int. Immunol.
γδ T cells: first line of defense and beyond
Annu. Rev. Immunol.
γδ T cells in cancer
Nat. Rev. Immunol.
Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism
Oncoimmunology
Vγ2Vδ2 TCR-dependent recognition of non-peptide antigens and Daudi cells analyzed by TCR gene transfer
J. Immunol.
Stimulation of human γδ T cells by nonpeptidic mycobacterial ligands
Science
Immunosurveillance by human γδ T lymphocytes: the emerging role of butyrophilins
F1000 Res.
Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells
Nat. Immunol.
Sensor function for butyrophilin 3A1 in prenyl pyrophosphate stimulation of human Vγ2Vδ2 T cells
J. Immunol.
Activation of human γδ T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor periplakin
J. Immunol.
Butyrophilin 3A/CD277-dependent activation of human γδ T cells: accessory cell capacity of distinct leukocyte populations
J. Immunol.
Ectopically expressed human tumor biomarker MutS homologue 2 is a novel endogenous ligand that is recognized by human γδ T cells to induce innate anti-tumor/virus immunity
J. Biol. Chem.
The promise of γδ T cells and the γδ T cell receptor for cancer immunotherapy
Cell. Mol. Immunol.
Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor
Nat. Immunol.
CD1d-lipid antigen recognition by the γδ TCR
Nat. Immunol.
Crystal structure of a γδ T-cell receptor specific for the human MHC class I homolog MICA
Proc. Natl. Acad. Sci. U. S. A.
Sensing of cell stress by human γδ TCR-dependent recognition of annexin A2
Proc. Natl. Acad. Sci. U. S. A.
NKG2D receptor and its ligands in host defense
Cancer Immunol. Res.
Activation of Vγ9Vδ2 T cells by NKG2D
J. Immunol.
Lysis of a broad range of epithelial tumour cells by human γδ T cells: involvement of NKG2D ligands and T-cell receptor- versus NKG2D-dependent recognition
Scand. J. Immunol.
Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications
Scand. J. Immunol.
Regulatory and effector functions of gamma-delta (γδ) T cells and their therapeutic potential in adoptive cellular therapy for cancer
Int. J. Cancer
Human T cell receptor γδ cells recognize endogenous mevalonate metabolites in tumor cells
J. Exp. Med.
Chemotherapy and zoledronate sensitize solid tumour cells to Vγ9Vδ2 T cell cytotoxicity
Cancer Immunol. Immunother.
Vγ9Vδ2 T lymphocytes efficiently recognize and kill zoledronate-sensitized, imatinib-sensitive, and imatinib-resistant chronic myelogenous leukemia cells
J. Immunol.
Zoledronate sensitizes neuroblastoma-derived tumor-initiating cells to cytolysis mediated by human γδ T cells
J. Immunother.
High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vγ9Vδ2 T-cell chemotaxis and cytotoxicity in vivo
Cancer Res.
Vδ1 T lymphocytes from B-CLL patients recognize ULBP3 expressed on leukemic B cells and up-regulated by trans-retinoic acid
Cancer Res.
Characterization of human γδ T lymphocytes infiltrating primary malignant melanomas
PLoS One
In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: a phase 1 study
Medicine
Delta One T cells for immunotherapy of chronic lymphocytic leukemia: clinical-grade expansion/differentiation and preclinical proof of concept
Clin. Cancer Res.
Phosphostim-activated γδ T cells kill autologous metastatic renal cell carcinoma
J. Immunol.
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2020, Molecular Therapy OncolyticsCitation Excerpt :Peripheral blood gamma delta (γδ) T cells that express γδ heterodimer of T cell receptor (TCR) chains are a minor population (1%–5% in healthy adults), the majority of which express the variable gene segments Vγ9 and Vδ2 (Vγ9Vδ2 T cells).1 Through their TCR, γδ T cells can recognize and interact in a non-MHC restricted fashion with tumor-associated antigens, including phosphoantigens that are produced during metabolic dysregulation in tumor cells.1–5 Once activated, γδ T cells exert potent effector functions to kill target cells by secreting cytotoxic molecules like granzyme and perforin, as well as involving the death receptor-ligand systems.
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