Neuroblastoma Killing Properties of Vδ2 and Vδ2-Negative γδT Cells Following Expansion by Artificial Antigen-Presenting Cells

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.