A Quantitative Deficiency in Peripheral Blood Vγ9Vδ2 Cells Is a Negative Prognostic Biomarker in Ovarian Cancer Patients

Vγ9Vδ2 cells are cytotoxic T cells that are able to recognize epithelial ovarian carcinoma (EOC) cells. Therefore, Vγ9Vδ2 cell-based adoptive transfer is an attractive therapy for EOC. However, the inefficient ex vivo expansion after specific stimulation of Vγ9Vδ2 cells from some patients and the relationships between Vγ9Vδ2 cells and clinical course of EOC are issues that remain to be clarified. Herein, peripheral blood mononuclear cells (PBMCs) from 60 EOC patients were stimulated with bromohydrin pyrophosphate (BrHPP) or zoledronate, which are specific agonists of Vγ9Vδ2 cells. The compounds differed in their efficacies to induce ex vivo Vγ9Vδ2 PBMC expansion, but 16/60 samples remained inefficiently expanded with both stimuli. Interestingly, the Vγ9Vδ2 cells in these low-responding PBMCs displayed before expansion (ex vivo PBMCs) an altered production of the pro-inflammatory cytokines IFN-γ and TNF-α, a decreased naive fraction and a reduced frequency. No evidence of an involvement of CD4(+)CD25(+)Foxp3(+) regulatory cells was observed. Importantly, our data also demonstrate that a Vγ9Vδ2 cell frequency of 0.35% or less in EOC PBMCs could be used to predict low responses to both BrHPP and zoledronate. Moreover, our data highlight that such a deficiency is not correlated with advanced EOC stages but is associated with more refractory states to platinum-based chemotherapy and is an independent predictor of shorter disease-free survival after treatment. These results are the first to suggest a potential contribution of Vγ9Vδ2 cells to the anti-tumor effects of chemotherapeutic agents and they strengthen interest in strategies that might increase Vγ9Vδ2 cells in cancer patients.