Discovery of chemotherapy‐associated ovarian cancer antigens by interrogating memory T cells

• Published in: International journal of cancer 2014-04, Vol.134 (8), p.1823-1834
• Main Authors: Paroli, Marino, Bellati, Filippo, Videtta, Melissa, Focaccetti, Chiara, Mancone, Carmine, Donato, Tiziana, Antonilli, Morena, Perniola, Giorgia, Accapezzato, Daniele, Napoletano, Chiara, Nuti, Marianna, Bartolazzi, Armando, Panici, Pierluigi Benedetti, Tripodi, Marco, Palombo, Fabio, Barnaba, Vincenzo
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antigens; Antigens, Neoplasm - immunology; Apoptosis; Apoptosis - immunology; Biological and medical sciences; Cancer; Cancer therapies; CD8-Positive T-Lymphocytes - immunology; Cell Survival; Chemotherapy; chemotherapy associated antigens; Dendritic Cells - immunology; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Hypotheses; Immunologic Memory - immunology; Immunology; Interferon-gamma - biosynthesis; Interleukin-17 - biosynthesis; Lymphocytes; Medical research; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - immunology; Proteins; Questioning; reverse immunology; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; T cell receptors; Th1 cells; Th1 Cells - immunology; Th17 cells; tumor biomarkers; Tumor Cells, Cultured; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28515

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. What's new? According to the immunogenic cell‐death hypothesis, chemotherapy can induce CD8+ and CD4+ T‐cell responses against tumor cells. The trigger is thought to be the release of additional tumor antigens from dying tumor cells. This paper describes a “reverse immunology” technique called a T‐cell interrogation system, for identifying chemotherapy‐associated antigens (CAAs) in ovarian cancer patients. Memory T cells that recognized antigens associated with apoptotic (but not live) OC cells were also correlated with prolonged survival in response to chemotherapy. This suggests that immune responses induced by immunogenic cell death may enhance current therapy.