Strategies to enhance cytotoxicity of tumor-infiltrating γδ T-cell subsets against autologous tumor cells

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Localization, distribution, cytotoxicity and activation state of human tumor-infiltrating γδ T cells (γδ TIL) and their impact on survival of cancer patients are of great interest for an improvement of γδ T cell-based immunotherapy. High recurrence rates in epithelial ovarian cancer (EOC) - even after successful initial surgical and poly-chemotherapeutic treatment - reflects a significant problem. Chemotherapeutic standard regimens are often not of long-lasting efficacy in the palliative situation. The presence of intra-tumoral cytotoxic T cells has been correlated with a favorable clinical outcome.Recently, we demonstrated an increased Vγ2,3,4 γδ T-cell infiltration co-expressing Vδ1- or Vδ3-chains in freshly isolated EOC tissue which strongly produce cytotoxic mediators such as granzyme A/B. Further, we discovered a novel role of TNF-related apoptosis-inducing ligand (TRAIL)-receptor 4 that enhance anti-tumoral Vδ1 T-cell cytotoxicity. Since central and effector memory Vδ1 TIL are increased within the EOC tissue, it is likely that they are activated at the tumor-site. The identification of site-specific occurrence of Vγ2,3,4 and Vγ9 γδ T-cell clones and a butyrophilin-dependent activation of Vγ9Vδ1and non-Vδ1/Vδ2 TIL will be investigated within the FOR2799.Our previous results demonstrated that the bispecific T cell engager (bsTCE) [(HER)2xVγ9] enhanced Vγ9 T-cell cytotoxicity against autologous EOC cells expressing the human epidermal growth factor receptor (HER)-2. Further, bsTCE partially overcomes intrinsic tumor resistance mechanisms which prevent γδ T-cell activation. Preliminary results revealed a 30-90% anti-tumor efficacy of [(HER)2xVγ9] in our novel patient-derived ex vivo tumor tissue model including an immunosuppressive tumor microenvironment (TME). Since Vγ2,3,4 TIL accumulate in the EOC tissue, we generated the bsTCE [(HER)2xVγ2,3,4], which allows in combination with [(HER)2xVγ9] to target up to 78% of the γδ TIL in EOC patients. The efficacy of [(HER)2xVγ2,3,4] on γδ T cell-mediated lysis of autologous EOC cells and the impact of the TME will be examined in the NSG mouse model and the patient-derived ex vivo tumor tissue model. The latter is of great use when trying to reduce the translational gap between preclinical and clinical research. The use of the bsTCE in the patient-derived ex vivo tumor tissue model also allows the targeted investigation of the effector function of Vγ2,3,4 and Vγ9 TIL. Since our bsTCEs do not induce γδ T-cell death like repetitive application of phosphorylated antigens does, this is a decisive advantage of bsTCE application. We expect that our bsTCEs reflect a novel tool for a future γδ T cell-based immunotherapy.