title: A quantitative deficiency in peripheral blood Vγ9Vδ2 cells is a negative prognostic biomarker in ovarian cancer patients.
abstract: 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.
authors.affiliation: Unité Mixe de Recherche Institut National de la Santé Et de la Recherche Médicale 991, Université de Rennes 1, Rennes, France. aurelie.thedrez@univ-rennes1.fr
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thedrez
authors.forename: Vincent
authors.initials: V
authors.lastname: Lavoué
authors.forename: Benoit
authors.initials: B
authors.lastname: Dessarthe
authors.forename: Pascale
authors.initials: P
authors.lastname: Daniel
authors.forename: Sébastien
authors.initials: S
authors.lastname: Henno
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jaffre
authors.forename: Jean
authors.initials: J
authors.lastname: Levêque
authors.forename: Véronique
authors.initials: V
authors.lastname: Catros
authors.forename: Florian
authors.initials: F
authors.lastname: Cabillic
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000276:immunology*; D017252:CD3 Complex / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D011756:Diphosphates / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D010051:Ovarian Neoplasms / Q000097:blood / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D014408:Biomarkers, Tumor; D017252:CD3 Complex; D011756:Diphosphates; D004164:Diphosphonates; D007093:Imidazoles; D014409:Tumor Necrosis Factor-alpha; C429553:bromohydrin pyrophosphate; D000077211:Zoledronic Acid; D007371:Interferon-gamma