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

Marino Paroli, Filippo Bellati, Melissa Videtta, Chiara Focaccetti, Carmine Mancone, Tiziana Donato, Morena Antonilli, Giorgia Perniola, Daniele Accapezzato, Chiara Napoletano, Marianna Nuti, Armando Bartolazzi, Pierluigi Benedetti Panici, Marco Tripodi, Fabio Palombo, Vincenzo Barnaba

Research output: Contribution to journalArticlepeer-review

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. 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.

Original languageEnglish
Pages (from-to)1823-1834
Number of pages12
JournalInternational Journal of Cancer
Volume134
Issue number8
DOIs
Publication statusPublished - Apr 15 2014

Keywords

  • chemotherapy associated antigens
  • ovarian cancer
  • reverse immunology
  • Th1 cells
  • Th17 cells
  • tumor biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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