title: Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs.
abstract: Major barriers to cancer therapy include the lack of selective inhibitors of regulatory T cells (Tregs) and the lack of broadly applicable ways to directly target tumors through frequently expressed surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is an attractive target protein because of its restricted abundance to highly immunosuppressive Tregsand oncogenic presence on human tumors. We characterized the effect of TNFR2 inhibition using antagonistic antibodies. In culture-based assays, we found that two TNFR2 antagonists inhibited Tregproliferation, reduced soluble TNFR2 secretion from normal cells, and enabled T effector cell expansion. The antagonistic activity occurred in the presence of added TNF, a natural TNFR2 agonist. These TNFR2 antibodies killed Tregsisolated from ovarian cancer ascites more potently than it killed Tregsfrom healthy donor samples, suggesting that these antibodies may have specificity for the tumor microenvironment. The TNFR2 antagonists also killed OVCAR3 ovarian cancer cells, which have abundant surface TNFR2. The antibodies stabilized antiparallel dimers in cell surface TNFR2 that rendered the receptor unable to activate the nuclear factor κB pathway and trigger cell proliferation. Our data suggest that, by targeting tumor cells and immunosuppressive tumor-associated Tregs, antagonistic TNFR2 antibodies may be an effective treatment for cancers positive for TNFR2.
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Torrey
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: John
authors.initials: J
authors.lastname: Butterworth
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mera
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Okubo
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Limei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Baum
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Defusco
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Plager
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Warden
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huang
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Vanamee
authors.affiliation: Department of Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Vincent Center for Reproductive Biology, Boston, MA 02114, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.affiliation: Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. faustman@helix.mgh.harvard.edu.
authors.forename: Denise L
authors.initials: DL
authors.lastname: Faustman
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D047889:Receptors, Tumor Necrosis Factor, Type II; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha