Review
. 2019 Sep;19(3).
doi: 10.1038/s41573-019-0038-z.

Translating gammadelta (γδ) T cells and their receptors into cancer cell therapies

Zsolt Sebestyen 1 Immo Prinz 2 Julie Déchanet-Merville 3 Bruno Silva-Santos 4 Jurgen Kuball 5 
Affiliations
  • PMID: 31492944
  •     165 References
  •     49 citations

Abstract

Clinical responses to checkpoint inhibitors used for cancer immunotherapy seemingly require the presence of αβT cells that recognize tumour neoantigens, and are therefore primarily restricted to tumours with high mutational load. Approaches that could address this limitation by engineering αβT cells, such as chimeric antigen receptor T (CAR T) cells, are being investigated intensively, but these approaches have other issues, such as a scarcity of appropriate targets for CAR T cells in solid tumours. Consequently, there is renewed interest among translational researchers and commercial partners in the therapeutic use of γδT cells and their receptors. Overall, γδT cells display potent cytotoxicity, which usually does not depend on tumour-associated (neo)antigens, towards a large array of haematological and solid tumours, while preserving normal tissues. However, the precise mechanisms of tumour-specific γδT cells, as well as the mechanisms for self-recognition, remain poorly understood. In this Review, we discuss the challenges and opportunities for the clinical implementation of cancer immunotherapies based on γδT cells and their receptors.

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γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation.
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γδ T Cells: Unexpected Regulators of Cancer Development and Progression.
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Murine CD27(-) Vγ6(+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages.
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TEG001 Insert Integrity from Vector Producer Cells until Medicinal Product.
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ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma.
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Cells, 2020 Mar 12; 9(3). PMID: 32155954    Free PMC article.
Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2+ T cells activities after hematopoietic transplantation for blood malignancies.
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Electroporation of NKG2D RNA CAR Improves Vγ9Vδ2 T Cell Responses against Human Solid Tumor Xenografts.
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Emerging Challenges of Preclinical Models of Anti-tumor Immunotherapeutic Strategies Utilizing Vγ9Vδ2 T Cells.
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Front Immunol, 2020 Jun 13; 11. PMID: 32528477    Free PMC article.
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The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy.
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Immune Signatures and Survival of Patients With Metastatic Melanoma, Renal Cancer, and Breast Cancer.
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Front Immunol, 2020 Jun 26; 11. PMID: 32582215    Free PMC article.
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Mistletoe-Extract Drugs Stimulate Anti-Cancer Vγ9Vδ2 T Cells.
Ling Ma, Swati Phalke, +2 authors, David Vermijlen.
Cells, 2020 Jul 02; 9(6). PMID: 32604868    Free PMC article.
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J Clin Invest, 2020 Jun 03; 130(9). PMID: 32484803    Free PMC article.
Engineering the Bridge between Innate and Adaptive Immunity for Cancer Immunotherapy: Focus on γδ T and NK Cells.
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Expansion With IL-15 Increases Cytotoxicity of Vγ9Vδ2 T Cells and Is Associated With Higher Levels of Cytotoxic Molecules and T-bet.
Pia Aehnlich, Ana Micaela Carnaz Simões, +2 authors, Per Thor Straten.
Front Immunol, 2020 Sep 29; 11. PMID: 32983105    Free PMC article.
Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study.
Kazuhiro Kakimi, Hirokazu Matsushita, +17 authors, Jun Nakajima.
J Immunother Cancer, 2020 Sep 20; 8(2). PMID: 32948652    Free PMC article.
Nano-Enhanced Cancer Immunotherapy: Immunology Encounters Nanotechnology.
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Aiming for the Sweet Spot: Glyco-Immune Checkpoints and γδ T Cells in Targeted Immunotherapy.
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Front Immunol, 2020 Nov 03; 11. PMID: 33133075    Free PMC article.
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Cancer immunotherapy with γδ T cells: many paths ahead of us.
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Cell Mol Immunol, 2020 Jul 24; 17(9). PMID: 32699351    Free PMC article.
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Ligand recognition by the γδ TCR and discrimination between homeostasis and stress conditions.
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TEG011 persistence averts extramedullary tumor growth without exerting off-target toxicity against healthy tissues in a humanized HLA-A*24:02 transgenic mice.
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J Leukoc Biol, 2020 Feb 06; 107(6). PMID: 32022317    Free PMC article.
Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring "Universal" Donor T Cells.
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Front Immunol, 2020 Dec 03; 11. PMID: 33262761    Free PMC article.
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Editorial: γδ T Cells in Cancer.
Seth B Coffelt, Dieter Kabelitz, +3 authors, Ilan Bank.
Front Immunol, 2020 Dec 18; 11. PMID: 33329597    Free PMC article.
Single-cell RNA sequencing of human breast tumour-infiltrating immune cells reveals a γδ T-cell subtype associated with good clinical outcome.
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Life Sci Alliance, 2020 Dec 04; 4(1). PMID: 33268347    Free PMC article.
Comparable Vδ2 Cell Functional Characteristics in Virally Suppressed People Living with HIV and Uninfected Individuals.
Matthew L Clohosey, Brendan T Mann, +4 authors, Natalia Soriano-Sarabia.
Cells, 2020 Dec 05; 9(12). PMID: 33271808    Free PMC article.
From thymus to periphery: Molecular basis of effector γδ-T cell differentiation.
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Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells.
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Cell Mol Immunol, 2020 Nov 26; 18(1). PMID: 33235387    Free PMC article.
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Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments.
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Nat Immunol, 2021 Jan 20; 22(2). PMID: 33462452    Free PMC article.
Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer.
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Functional and metabolic dichotomy of murine γδ T cell subsets in cancer immunity.
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Eur J Immunol, 2020 Nov 15; 51(1). PMID: 33188652    Free PMC article.
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The BTLA and PD-1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells.
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Immun Inflamm Dis, 2020 Dec 18; 9(1). PMID: 33332777    Free PMC article.
Chimeric Antigen Receptor beyond CAR-T Cells.
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Brain Tumor Microenvironment and Angiogenesis in Melanoma Brain Metastases.
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Front Oncol, 2021 Feb 09; 10. PMID: 33552976    Free PMC article.
αβ T-cell graft depletion for allogeneic HSCT in adults with hematological malignancies.
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Blood Adv, 2021 Feb 12; 5(1). PMID: 33570642    Free PMC article.
Vγ9Vδ2 T cells strengthen cisplatin inhibition activity against breast cancer MDA-MB-231 cells by disrupting mitochondrial function and cell ultrastructure.
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Adoptive cell therapy of patient-derived renal cell carcinoma xenograft model with IL-15-induced γδT cells.
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Phase II Trial of Maintenance Treatment With IL2 and Zoledronate in Multiple Myeloma After Bone Marrow Transplantation: Biological and Clinical Results.
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Taking T-Cell Oncotherapy Off-the-Shelf.
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The Dual Roles of Human γδ T Cells: Anti-Tumor or Tumor-Promoting.
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An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation.
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Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective.
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Epigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T cell-mediated cytotoxicity in lung cancer.
Rueyhung R Weng, Hsuan-Hsuan Lu, +17 authors, Hsing-Chen Tsai.
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γδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde.
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