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Open AccessArticle

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

Department of Pediatric Hematology and Oncology, University Children’s Hospital Tuebingen, Hoppe-Seyler Street 1, 72076 Tübingen, Germany
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Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 130; https://doi.org/10.3390/cancers12010130
Received: 25 November 2019 / Revised: 13 December 2019 / Accepted: 30 December 2019 / Published: 4 January 2020
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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. View Full-Text
Keywords: γδ T cells; IL-12; IL-18; senescence; TCR bypass stimulation γδ T cells; IL-12; IL-18; senescence; TCR bypass stimulation
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Schilbach, K.; Welker, C.; Krickeberg, N.; Kaißer, C.; Schleicher, S.; Hashimoto, H. 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. Cancers 2020, 12, 130.

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