title: Changes in ovarian tumor cell number, tumor vasculature, and T cell function monitored in vivo using a novel xenograft model.
abstract: Despite an initial response to chemotherapy, most patients with ovarian cancer eventually progress and succumb to their disease. Understanding why effector T cells that are known to infiltrate the tumor do not eradicate the disease after cytoreduction is critically important to the development of novel therapeutic strategies to augment tumor immunity and improve patient outcomes. Such studies have been hampered by the lack of a suitable in vivo model. We report here a simple and reliable model system in which ovarian tumor cell aggregates implanted intraperitoneally into severely immunodeficient NSG mice establish tumor microenvironments within the omentum. The rapid establishment of tumor xenografts within this small anatomically well-defined site enables the recovery, characterization, and quantification of tumor and tumor-associated T cells. We validate here the ability of the omental tumor xenograft (OTX) model to quantify changes in tumor cell number in response to therapy, to quantify changes in the tumor vasculature, and to demonstrate and study the immunosuppressive effects of the tumor microenvironment. Using the OTX model, we show that the tumor-associated T cells originally present within the tumor tissues are anergic and that fully functional autologous T cells injected into tumor-bearing mice localize within the tumor xenograft. The transferred T cells remain functional for up to 3 days within the tumor microenvironment but become unresponsive to activation after 7 days. The OTX model provides for the first time the opportunity to study in vivo the cellular and molecular events contributing to the arrest in T cell function in human ovarian tumors.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Yokota
authors.forename: John G
authors.initials: JG
authors.lastname: Facciponte
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kelleher
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Jenni L
authors.initials: JL
authors.lastname: Loyall
authors.forename: Robert R
authors.initials: RR
authors.lastname: Parsons
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: John G
authors.initials: JG
authors.lastname: Frelinger
authors.forename: Edith M
authors.initials: EM
authors.lastname: Lord
authors.forename: Scott A
authors.initials: SA
authors.lastname: Gerber
authors.forename: Sathy V
authors.initials: SV
authors.lastname: Balu-Iyer
authors.forename: Richard B
authors.initials: RB
authors.lastname: Bankert
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D007120:Immunochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D059016:Tumor Microenvironment
keywords: human ovarian tumor microenvironment; tumor-associated T cells