期刊
CLINICAL CANCER RESEARCH
卷 20, 期 22, 页码 5720-5732出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-3464
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资金
- Wellcome Trust
- Dubois Childhood Cancer Research Fund
- Leukaemia and Lymphoma Research
- Great Ormond Street Hospital Charity
- Great Ormond Street Hospital Biomedical Research Centre
- Cancer Research UK [14779] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1243, V4015] Funding Source: researchfish
- Sparks Charity [12WTICH13 - DCCF] Funding Source: researchfish
Purpose: The majority of circulating human gamma delta T lymphocytes are of the V gamma 9V delta 2 lineage, and have T-cell receptor (TCR) specificity for nonpeptide phosphoantigens. Previous attempts to stimulate and expand these cells have therefore focused on stimulation using ligands of the V gamma 9V delta 2 receptor, whereas relatively little is known about variant blood gamma delta T subsets and their potential role in cancer immunotherapy. Experimental Design: To expand the full repertoire of gamma delta T without bias toward specific TCRs, we made use of artificial antigen-presenting cells loaded with an anti gamma delta TCR antibody that promoted unbiased expansion of the gamma delta T repertoire. Expanded cells from adult blood donors were sorted into 3 populations expressing respectively V delta 2 TCR chains (Vd2(+)), V delta 1 chains (V delta 1(+)), and TCR of other delta chain subtypes (V delta 1(neg)V delta 2(neg)). Results: Both freshly isolated and expanded cells showed heterogeneity of differentiation markers, with a less differentiated phenotype in the V delta 1 and V delta 1(neg)V delta 2(neg) populations. Expanded cells were largely of an effector memory phenotype, although there were higher numbers of less differentiated cells in the V delta 1(+) and V delta 1(neg)V delta 2(neg) populations. Using neuroblastoma tumor cells and the anti-GD2 therapeutic mAb ch14.18 as a model system, all three populations showed clinically relevant cytotoxicity. Although killing by expanded V delta 2 cells was predominantly antibody dependent and proportionate to upregulated CD16, V delta 1 cells killed by antibody-independent mechanisms. Conclusions: In conclusion, we have demonstrated that polyclonal-expanded populations of gamma delta T cells are capable of both antibody-dependent and -independent effector functions in neuroblastoma. Clin Cancer Res; 20(22); 5720-32. (C) 2014 AACR.
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