Trends in Immunology
Volume 38, Issue 9, September 2017, Pages 668-678
Journal home page for Trends in Immunology

Review
The Ambiguous Role of γδ T Lymphocytes in Antitumor Immunity

https://doi.org/10.1016/j.it.2017.06.004Get rights and content

Trends

γδ T cells are a subset of T cells that are relatively abundant at barrier sites such as the skin and intestine.

γδ T cells sense malignant cells via their T cell receptor (TCR) and the NKG2D receptor, but are not MHC-restricted to tumor-specific antigens, and hence have emerged as candidates for cellular immunotherapy.

Tumor-infiltrating γδ T cells can also promote tumorigenesis through different mechanisms, including IL-17 production and upregulation of PD-L1.

Emerging concepts aim at enhancing the antitumor activity of γδ T cells (e.g., through tumor-targeting bispecific antibodies) while simultaneously preventing the protumorigenic activities of γδ T cells (e.g., through anti-PD-L1 and/or anti-IL-17 antibodies).

γδ T cells play a role in immune surveillance because they recognize stress-induced surface molecules and metabolic intermediates that are frequently dysregulated in transformed cells. Hence, γδ T cells have attracted much interest as effector cells in cell-based immunotherapy. Recently, however, it has been realized that γδ T cells can also promote tumorigenesis through various mechanisms including regulatory activity and IL-17 production. In this review we outline both the pathways involved in cancer cell recognition and killing by γδ T cells as well as current evidence for their protumorigenic activity in various models. Finally, we discuss strategies to improve the tumor reactivity of γδ T cells and to counteract their protumorigenic activities, which should open improved perspectives for their clinical application.

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)

  • A. Noguchi

    Zoledronate-activated Vγ9 γδ T cell-based immunotherapy is feasible and restores the impairment of γδ T cells in patients with solid tumors

    Cytotherapy

    (2011)
  • D. Hannani

    Harnessing γδ T cells in anticancer immunotherapy

    Trends Immunol.

    (2012)
  • J.H. Park

    CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date

    Blood

    (2016)
  • G. Peng

    Tumor-infiltrating γδ T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway

    Immunity

    (2007)
  • P. Wu

    γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer

    Immunity

    (2014)
  • E.L. Reinherz

    αβ TCR-mediated recognition: relevance to tumor-antigen discovery and cancer immunotherapy

    Cancer Immunol. Res.

    (2015)
  • T. Hinz

    Identification of the complete expressed human TCR Vγ repertoire by flow cytometry

    Int. Immunol.

    (1997)
  • Y.H. Chien

    γδ T cells: first line of defense and beyond

    Annu. Rev. Immunol.

    (2014)
  • B. Silva-Santos

    γδ T cells in cancer

    Nat. Rev. Immunol.

    (2015)
  • G. Gruenbacher

    Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism

    Oncoimmunology

    (2014)
  • J.F. Bukowski

    Vγ2Vδ2 TCR-dependent recognition of non-peptide antigens and Daudi cells analyzed by TCR gene transfer

    J. Immunol.

    (1995)
  • P. Constant

    Stimulation of human γδ T cells by nonpeptidic mycobacterial ligands

    Science

    (1994)
  • D. Kabelitz

    Immunosurveillance by human γδ T lymphocytes: the emerging role of butyrophilins

    F1000 Res.

    (2017)
  • S. Vavassori

    Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells

    Nat. Immunol.

    (2013)
  • H. Wang et al.

    Sensor function for butyrophilin 3A1 in prenyl pyrophosphate stimulation of human Vγ2Vδ2 T cells

    J. Immunol.

    (2015)
  • D.A. Rhodes

    Activation of human γδ T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor periplakin

    J. Immunol.

    (2015)
  • P.T. Nerdal

    Butyrophilin 3A/CD277-dependent activation of human γδ T cells: accessory cell capacity of distinct leukocyte populations

    J. Immunol.

    (2016)
  • Y. Dai

    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.

    (2012)
  • M. Legut

    The promise of γδ T cells and the γδ T cell receptor for cancer immunotherapy

    Cell. Mol. Immunol.

    (2015)
  • C.R. Willcox

    Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor

    Nat. Immunol.

    (2012)
  • A.P. Uldrich

    CD1d-lipid antigen recognition by the γδ TCR

    Nat. Immunol.

    (2013)
  • B. Xu

    Crystal structure of a γδ T-cell receptor specific for the human MHC class I homolog MICA

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • R. Marlin

    Sensing of cell stress by human γδ TCR-dependent recognition of annexin A2

    Proc. Natl. Acad. Sci. U. S. A.

    (2017)
  • L.L. Lanier

    NKG2D receptor and its ligands in host defense

    Cancer Immunol. Res.

    (2015)
  • B. Rincon-Orozco

    Activation of Vγ9Vδ2 T cells by NKG2D

    J. Immunol.

    (2005)
  • P. Wrobel

    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.

    (2007)
  • G. Chitadze

    Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications

    Scand. J. Immunol.

    (2013)
  • S. Paul et al.

    Regulatory and effector functions of gamma-delta (γδ) T cells and their therapeutic potential in adoptive cellular therapy for cancer

    Int. J. Cancer

    (2016)
  • H.J. Gober

    Human T cell receptor γδ cells recognize endogenous mevalonate metabolites in tumor cells

    J. Exp. Med.

    (2003)
  • S.R. Mattarollo

    Chemotherapy and zoledronate sensitize solid tumour cells to Vγ9Vδ2 T cell cytotoxicity

    Cancer Immunol. Immunother.

    (2007)
  • M. D’Asaro

    Vγ9Vδ2 T lymphocytes efficiently recognize and kill zoledronate-sensitized, imatinib-sensitive, and imatinib-resistant chronic myelogenous leukemia cells

    J. Immunol.

    (2010)
  • N. Nishio

    Zoledronate sensitizes neuroblastoma-derived tumor-initiating cells to cytolysis mediated by human γδ T cells

    J. Immunother.

    (2012)
  • I. Benzaïd

    High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vγ9Vδ2 T-cell chemotaxis and cytotoxicity in vivo

    Cancer Res.

    (2011)
  • A. Poggi

    Vδ1 T lymphocytes from B-CLL patients recognize ULBP3 expressed on leukemic B cells and up-regulated by trans-retinoic acid

    Cancer Res.

    (2004)
  • A. Cordova

    Characterization of human γδ T lymphocytes infiltrating primary malignant melanomas

    PLoS One

    (2012)
  • J.G. Pressey

    In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: a phase 1 study

    Medicine

    (2016)
  • A.R. Almeida

    Delta One T cells for immunotherapy of chronic lymphocytic leukemia: clinical-grade expansion/differentiation and preclinical proof of concept

    Clin. Cancer Res.

    (2016)
  • E. Viey

    Phosphostim-activated γδ T cells kill autologous metastatic renal cell carcinoma

    J. Immunol.

    (2005)
  • Cited by (63)

    • Resident human dermal γδT-cells operate as stress-sentinels: Lessons from the hair follicle

      2021, Journal of Autoimmunity
      Citation Excerpt :

      These data show that γδT-cells isolated from human dermis are attracted to infiltrate the epithelium of autologous stressed HFs, most likely in a CXCL12-dependent fashion, and that cell-cell contact may be necessary for γδT-cell-induced HF cytotoxicity. Vδ1+ T-cells can exhibit cytotoxicity after recognizing CD1d-presented lipid antigens [3,16,61,62,73] and by binding to stress-induced molecules such as MICA [74,75]. This also results in IFN-γ secretion [65,76], the only cytokine currently known to potently induce human HF-IP collapse [36,50,51].

    • Electroporation of NKG2D RNA CAR Improves Vγ9Vδ2 T Cell Responses against Human Solid Tumor Xenografts

      2020, Molecular Therapy Oncolytics
      Citation 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.

    • γδ T cells: origin and fate, subsets, diseases and immunotherapy

      2023, Signal Transduction and Targeted Therapy
    View all citing articles on Scopus
    View full text