Engineering Approaches in Human Gamma Delta T Cells for Cancer Immunotherapy

Fisher, Jonathan; Anderson, John

doi:10.3389/fimmu.2018.01409

Cited by 56 publications

(47 citation statements)

References 119 publications

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“…Recently, attempts have been made to equip these already versatile innate-like T cells with additional functions. Using genetic manipulation, chimeric antigen receptors (CARs) or αβ T cell-derived TCRs have been transferred to γδ T cells in order to combine tissue-resident biology and innate target recognition with antigen-specific activation and selection [87]. Along the same line, Vγ9Vδ2 T cells have been genetically engineered to acquire chemotherapy resistance enabling the combined administration of chemo-and immunotherapy [88].…”

Section: Discussionmentioning

confidence: 99%

Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance

Nussbaumer

Thurnher

2020

Cells

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Butyrophilin and butyrophilin-like proteins select γδ T cells and direct the migration of γδ T cell subsets to distinct anatomical sites. γδ T cells expressing Vδ2 paired with Vγ9 (Vγ9Vδ2 T cells) are the predominant γδ T cell type in human peripheral blood. Vγ9Vδ2 T cells, which cannot be studied easily in vivo because they do not exist in rodents, are often referred to as innate-like T cells. The genetically recombined γδ T cell receptor (TCR) that responds to isoprenoid-derived pyrophosphates (phosphoantigens) produced by infected and malignant cells in a butyrophilin-dependent manner qualifies them as therapeutically relevant components of the adaptive immune system. On the other hand, cell-surface proteins such as the C-type lectin CD161 mark a functional phenotype of Vγ9Vδ2 T cells that mediates TCR-independent innate-like responses. Moreover, CD56 (neural cell adhesion molecule, NCAM) and the G protein-coupled receptor GPR56 define Vγ9Vδ2 T cells with increased cytolytic potential and, like CD161, may also be expressed by dendritic cells, principally facilitating the generation of an innate-like immunological synapse. In this review, we summarise current knowledge of Vγ9Vδ2 T cell functional phenotypes that are critical to lymphoid stress surveillance.

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Section: Discussionmentioning

confidence: 99%

Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance

Nussbaumer

Thurnher

2020

Cells

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“…Protocols for the generation and transfer of cytokine-activated Vδ1 + γδ T cells, so called DOT cells, have been established by Silva-Santos's group and have already been proven to be safe [53]. Analogously patient-derived γδ T cells [54] or donor-derived γδ T cells for hematopoietic stem cell transplantation [55] can be isolated according to GMP guidelines by "negative selection", i.e., αβ T cell depletion from peripheral blood or mobilized donors' apheresis. Such γδ T cells could be ex vivo stimulated with IL-2, IL-12, and IL-18, thereby omitting the unwanted side effects of the systemic administration of cytokines.…”

Section: Discussionmentioning

confidence: 99%

In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

Schilbach

Welker

Krickeberg

et al. 2020

Cancers

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Abundant IFN-γ secretion, potent cytotoxicity, and major histocompatibility complex-independent targeting of a large spectrum of tumors make γδ T cells attractive candidates for cancer immunotherapy. Upon tumor recognition through the T-cell receptor (TCR), NK-receptors, or NKG2D, γδ T cells generate the pro-inflammatory cytokines TNF-α and IFN-γ, or granzymes and perforin that mediate cellular apoptosis. Despite these favorable potentials, most clinical trials testing the adoptive transfer of pharmacologically TCR-targeted and expanded γδ T cells resulted in a limited response. Recently, the TCR-independent activation of γδ T cells was identified. However, the modulation of γδ T cell’s effector functions solely by cytokines remains to be elucidated. In the present study, we systematically analyzed the impact of IL-2, IL-12, and IL-18 in parallel with TCR stimulation on proliferation, cytokine production, and anti-tumor activity of γδ T cells. Our results demonstrate that IL-12 and IL-18, when combined, constitute the most potent stimulus to enhance anti-tumor activity and induce proliferation and IFN-γ production by γδ T cells in the absence of TCR signaling. Intriguingly, stimulation with IL-12 and IL-18 without TCR stimulus induces a comparable degree of anti-tumor activity in γδ T cells to TCR crosslinking by killing tumor cells and driving cancer cells into senescence. These findings approve the use of IL-12/IL-18-stimulated γδ T cells for adoptive cell therapy to boost anti-tumor activity by γδ T cells.

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“…Whilst these combined features of γδ T cells make them an attractive source for unmodified cell-based adoptive immunotherapy approaches, γδ T cells may also be harnessed for genetic manipulation. Either as a vehicle for chimeric antigen receptors (CARs) or αβ T cell-derived TCRs [90], γδ T cells could combine tissue resident biology and innate target recognition with antigen-specific activation and selection. Furthermore, a better understanding of γδ Τ cell interaction with BTN/BTNL molecules, as well as their regulation and activation in normal tissues and tumors, may allow for therapeutic manipulation in situ using targeted or checkpoint therapies.…”

Section: Discussionmentioning

confidence: 99%

The emerging role of γδ T cells in cancer immunotherapy

Nussbaumer¹,

Koslowski²

2019

Immuno-Oncology Technology

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The recent successes of chimeric antigen receptor T cells in the treatment of hematological malignancies have clearly led to an explosion in the field of adoptive cell therapy for cancer. Current efforts are focused on the translation of this exciting technology to the treatment of solid tumors and the development of allogeneic 'off-theshelf' therapies. γδ T cells are currently gaining considerable attention in this field as their unique biology and established role in cancer immunosurveillance place them in a unique position to potentially overcome these challenges in adoptive cell therapy. Here, we review the relevant aspects of the function of γδ T cells in cancer immunity, and summarize clinical observations and clinical trial results that highlight their emerging role as a platform for the development of safe and effective cancer immunotherapies.

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Engineering Approaches in Human Gamma Delta T Cells for Cancer Immunotherapy

Cited by 56 publications

References 119 publications

Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance

Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance

In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

The emerging role of γδ T cells in cancer immunotherapy

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