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

Abstract

Purpose: The majority of circulating human gdT lymphocytes are of the Vg9Vd2 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 Vg9Vd2 receptor, whereas relatively little is known about variant blood gdT subsets and their potential role in cancer immunotherapy.Experimental Design: To expand the full repertoire of gdT without bias toward specific TCRs, we made use of artificial antigen-presenting cells loaded with an anti gdTCR antibody that promoted unbiased expansion of the gdT repertoire. Expanded cells from adult blood donors were sorted into 3 populations expressing respectively Vd2 TCR chains (Vd2

Adoptively transferred Vγ9Vδ2 T cells show potent antitumor effects in a preclinical B cell lymphomagenesis model

“…The mechanisms responsible for activating Vδ2 + T cells are better understood than those of Vδ1 + T cells, and therefore the Vδ2 + subset has been more extensively investigated for immunotherapy. Functional responses of Vδ2 + T cells can be initiated by at least 3 distinct recognition pathways: (a) via the TCR, (b) via natural killer (NK) family receptors such as NKG2D, and (c) via Fc receptor (CD16) binding to antibody-coated target cells (10). Each of these pathways may facilitate their antitumor responses.…”

Avoidance of On-Target Off-Tumor Activation Using a Co-stimulation-Only Chimeric Antigen Receptor

“…For Vd2 + gdT cell cytotoxicity against neuroblastoma, co-stimulation is known to occur in part through receptors, such as NKG2D, which are ligated by danger-associated molecules, such as MIC-A and MIC-B, but can also be provided via Fcg receptors within the context of an opsonized target cell, as we have previously shown. 19,20 The degree of antibody-dependent cell-mediated cytotoxicity (ADCC) was proportional to the degree of antigen-antibody-CD16 interaction. 19,20 Neuroblastoma cells have been reported to evade NKG2D-mediated immune destruction through downregulation of NKG2D ligands or by secretion of receptor-blocking soluble ligands.…”

“…19,20 The degree of antibody-dependent cell-mediated cytotoxicity (ADCC) was proportional to the degree of antigen-antibody-CD16 interaction. 19,20 Neuroblastoma cells have been reported to evade NKG2D-mediated immune destruction through downregulation of NKG2D ligands or by secretion of receptor-blocking soluble ligands. 21,22 This has been demonstrated to be an important escape mechanism against NK cellmediated killing of neuroblastoma.…”

“…The lack of IFN-g production in the absence of a second signal in the neuroblastoma model is consistent with our previously published findings, which demonstrated the need to coat neuroblastoma cells with antibodies that sensitize to ADCC to generate an optimal IFN-g response in Vd2 T cells. 20 Future characterization of other co-stimulatory endodomains within the co-stimulation-only CAR architecture will explain if intracellular detection of TNF-a, upon engagement of the GD2-DAP10 CAR without TCR engagement, is due to the endodomain chosen here, i.e., DAP10, which has previously been associated with TNF-a production after NKG2D activation. 36 We have demonstrated that the GD2-DAP10 CAR can induce Vd2 + gdT cell cytotoxicity only against cell lines that engage both the gdTCR and the CAR, providing more precise control than conventional CD3z-containing CARs, which induce cytotoxicity in the presence of target antigen alone.…”

Promising Cell-Based Immunotherapy Using Gamma Delta T Cells: Together Is Better

“…In this issue of Clinical Cancer Research, the articles by Deniger and colleagues (1) and by Fisher and colleagues (2) report on a novel process for scaling up in vitro expansion of polyclonal gd T-cell lines with killing activity against cancer cells for clinical use. T-cell therapy to treat cancer has been the focus of much interest in the past years and led to the recent success of chimeric antigen receptors-expressing T cells (reviewed in ref.…”