title: Discovery of chemotherapy-associated ovarian cancer antigens by interrogating memory T cells.
abstract: According to the immunogenic cell death hypothesis, clinical chemotherapy treatments may result in CD8(+) and CD4(+) T-cell responses against tumor cells. To discover chemotherapy-associated antigens (CAAs), T cells derived from ovarian cancer (OC) patients (who had been treated with appropriate chemotherapy protocols) were interrogated with proteins isolated from primary OC cells. We screened for immunogenicity using two-dimensional electrophoresis gel-eluted OC proteins. Only the selected immunogenic antigens were molecularly characterized by mass-spectrometry-based analysis. Memory T cells that recognized antigens associated with apoptotic (but not live) OC cells were correlated with prolonged survival in response to chemotherapy, supporting the model of chemotherapy-induced apoptosis as an adjuvant of anti-tumor immunity. The strength of both memory CD4(+) and CD8(+) T cells producing either IFN-γ or IL-17 in response to apoptotic OC antigens was also significantly greater in Responders to chemotherapy than in nonresponders. Immunogenicity of some of these antigens was confirmed using recombinant proteins in an independent set of patients. The T-cell interrogation system represents a strategy of reverse tumor immunology that proposes to identify CAAs, which may then be validated as possible prognostic tumor biomarkers or cancer vaccines.
authors.affiliation: Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, Rome, Italy.
authors.forename: Marino
authors.initials: M
authors.lastname: Paroli
authors.forename: Filippo
authors.initials: F
authors.lastname: Bellati
authors.forename: Melissa
authors.initials: M
authors.lastname: Videtta
authors.forename: Chiara
authors.initials: C
authors.lastname: Focaccetti
authors.forename: Carmine
authors.initials: C
authors.lastname: Mancone
authors.forename: Tiziana
authors.initials: T
authors.lastname: Donato
authors.forename: Morena
authors.initials: M
authors.lastname: Antonilli
authors.forename: Giorgia
authors.initials: G
authors.lastname: Perniola
authors.forename: Daniele
authors.initials: D
authors.lastname: Accapezzato
authors.forename: Chiara
authors.initials: C
authors.lastname: Napoletano
authors.forename: Marianna
authors.initials: M
authors.lastname: Nuti
authors.forename: Armando
authors.initials: A
authors.lastname: Bartolazzi
authors.forename: Pierluigi Benedetti
authors.initials: PB
authors.lastname: Panici
authors.forename: Marco
authors.initials: M
authors.lastname: Tripodi
authors.forename: Fabio
authors.initials: F
authors.lastname: Palombo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Barnaba
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D018417:Th1 Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D020381:Interleukin-17; D007371:Interferon-gamma
keywords: Th1 cells; Th17 cells; chemotherapy associated antigens; ovarian cancer; reverse immunology; tumor biomarkers