Abstract
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.
Highlights
Introduction γδT cells constitute a major group of T cells categorized as innate that respond rapidly to antigens and manifest immediate effector functions
To determine the individual and synergistic effect of IL-2, IL-12 and IL-18 on the proliferation of γδ γδ T cells, untouched isolated CFSE-labelled γδ T cells were treated with T-cell receptor (TCR) stimulus through the Tcells, untouched isolated CFSE-labelled γδ T cells were treated with TCR stimulus through the pan-γδ pan-γδ antibody IMMU510 and or the cytokines, IL-2, IL-12, IL-18, or combinations thereof
Cells is exclusively dependent on cytokines and not involving TCR activation, and occurs in the periphery, we systematically analyzed the impact of IL-2, IL-12, and IL-18 alone and combined, in the presence and absence of TCR stimulation. The results from this comparative study demonstrate that the combined stimulation of γδ T cells via IL-2/IL-12/IL-18 is the most potent stimulus to enhance anti-tumor activity, proliferation and IFN-γ production in γδ T cells in the absence of TCR ligation
Summary
Introduction γδT cells constitute a major group of T cells categorized as innate that respond rapidly to antigens and manifest immediate effector functions. Vδ1+ γδ T cells recognize major histocompatibility complex (MHC) class I chain-related protein A and B (MICA and MICB), as well as foreign/self-lipid presented by non-classical MHC molecules like CD1 family [2]. Since they are activated during the early phases of infection or inflammation before effective adaptive immune responses develop and are transmitters of critical signals to activate the adaptive immune system, they act as a bridge between the innate and adaptive. Efforts to harness γδ T cells for clinical contexts, mostly by the adoptive transfer of ex vivo activated and expanded γδ T cells, have been tested for various types of cancers, but most trials have resulted in limited clinical efficacy [3,4,5,6,7,8,9,10,11]
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