title: Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine-Dependent Arrest in the T-cell Signaling Cascade.
abstract: The identification of immunosuppressive factors within human tumor microenvironments, and the ability to block these factors, would be expected to enhance patients' antitumor immune responses. We previously established that an unidentified factor, or factors, present in ovarian tumor ascites fluids reversibly inhibited the activation of T cells by arresting the T-cell signaling cascade. Ultracentrifugation of the tumor ascites fluid has now revealed a pellet that contains small extracellular vesicles (EV) with an average diameter of 80 nm. The T-cell arrest was determined to be causally linked to phosphatidylserine (PS) that is present on the outer leaflet of the vesicle bilayer, as a depletion of PS-expressing EV or a blockade of PS with anti-PS antibody significantly inhibits the vesicle-induced signaling arrest. The inhibitory EV were also isolated from solid tumor tissues. The presence of immunosuppressive vesicles in the microenvironments of ovarian tumors and our ability to block their inhibition of T-cell function represent a potential therapeutic target for patients with ovarian cancer.
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kelleher
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Sathy
authors.initials: S
authors.lastname: Balu-Iyer
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York.
authors.forename: Jenni
authors.initials: J
authors.lastname: Loyall
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Sacca
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York.
authors.forename: Gautam N
authors.initials: GN
authors.lastname: Shenoy
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York.
authors.forename: Peng
authors.initials: P
authors.lastname: Peng
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Vandana
authors.initials: V
authors.lastname: Iyer
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Fathallah
authors.affiliation: School of Medicine, Infectious Disease Division, University at Buffalo, Buffalo, New York, and Department of Veteran Affairs, Western New York Health Care System, Buffalo, New York.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Berenson
authors.affiliation: Department of Flow Cytometry, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Wallace
authors.affiliation: Department of Flow Cytometry, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tario
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York. rbankert@buffalo.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Bankert
mesh_terms: D001201:Ascites / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000067128:Extracellular Vesicles / Q000276:immunology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D008055:Lipids / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology*; D010718:Phosphatidylserines / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D008055:Lipids; D010718:Phosphatidylserines