title: Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: implications for immunotherapy.
abstract: Epithelial ovarian cancer (EOC) usually spreads into the peritoneal cavity, thereby providing an opportunity for intraperitoneal adoptive immunotherapy with Vγ9Vδ2 T lymphocytes, a T cell subpopulation endowed with high lytic properties against tumor cells. However, previous studies have reported that Vγ9Vδ2 T cells fail to expand from peripheral blood mononuclear cells in one-third of patients with cancer. Here, from a cohort of 37 patients with EOC, a multiple correspondence analysis identified three populations, one of which was not suitable for Vγ9Vδ2 T-cell adoptive therapy. Interestingly, the ineligible patients were identified based on the frequency of Vγ9Vδ2 T cells in their peripheral blood and the patients' age. The average time to tumor recurrence was also found to be significantly different between the three populations, suggesting that the innate immune response is involved in EOC prognosis. A dramatic decrease in the lytic properties of Vγ9Vδ2 T cells occurred following incubation with ascitic supernatant and was found to be associated with reduced perforin/granzyme degranulation. Prostaglandin E2, but not IL-6, IL-10, VEGF or TGF-β, showed immunosuppressive effects in Vγ9Vδ2 T cells. Interestingly, our results emphasize that pretreating ovarian tumor cells with zoledronate partially reverses the immunosuppressive effects of ovarian cancer-associated ascites and restores a high level of lytic activity. These data sustain that optimal Vγ9Vδ2 T-cell adoptive immunotherapy previously requires counteracting the tumor immunosuppressive microenvironment. Altogether, our findings provide a rationale for clinically evaluating Vγ9Vδ2 T-cell adoptive immunotherapy with intraperitoneal carcinomatosis presensitization by zoledronate in patients with EOC.
authors.affiliation: Université de Rennes 1, Rennes, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lavoué
authors.forename: Florian
authors.initials: F
authors.lastname: Cabillic
authors.forename: Olivier
authors.initials: O
authors.lastname: Toutirais
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thedrez
authors.forename: Benoît
authors.initials: B
authors.lastname: Dessarthe
authors.forename: Cécile Thomas
authors.initials: CT
authors.lastname: de La Pintière
authors.forename: Pascale
authors.initials: P
authors.lastname: Daniel
authors.forename: Fabrice
authors.initials: F
authors.lastname: Foucher
authors.forename: Estelle
authors.initials: E
authors.lastname: Bauville
authors.forename: Sébastien
authors.initials: S
authors.lastname: Henno
authors.forename: Florence
authors.initials: F
authors.lastname: Burtin
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Bansard
authors.forename: Jean
authors.initials: J
authors.lastname: Levêque
authors.forename: Véronique
authors.initials: V
authors.lastname: Catros
authors.forename: Françoise
authors.initials: F
authors.lastname: Bouet-Toussaint
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001201:Ascites / Q000503:physiopathology; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000502:physiology*; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007167:Immunotherapy; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000473:pathology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000077211:Zoledronic Acid
chemical_list: D000911:Antibodies, Monoclonal; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D015232:Dinoprostone