Protein disulfide isomerase A3-specific Th1 effector cells infiltrate colon cancer tissue of patients with circulating anti-protein disulfide isomerase A3 autoantibodies

Cristiana Caorsi, Elena Niccolai, Michela Capello, Rosario Vallone, Michelle S. Chattaragada, Brunilda Alushi, Anna Castiglione, Gianni Ciccone, Alessandro Mautino, Paola Cassoni, Lucia De Monte, Sheila M. Álvarez-Fernández, Amedeo Amedei, Massimo Alessio, Francesco Novelli

Research output: Contribution to journalArticle

Abstract

To investigate novel colorectal cancer (CRC)-associated antigens that could be targets of humoral or cellular responses, we analyzed the reactivity of serum from a long-surviving CRC patient (for more than 100 months of follow-up) in clinical remission, by serologic proteome analysis. Two-dimensional Western blotting (2D-WB) and mass spectrometry analysis revealed a strong reactivity of this serum against protein disulfide isomerase A3 (PDIA3). Anti-PDIA3 antibodies are not a diagnostic marker of CRC, 2D-WB and Luminex analysis revealed that they were equally present in about 10% of sera from healthy subjects and CRC patients. Kaplan-Meier analysis of survival in CRC patient cohort, after 48 months of follow-up, showed a trend of higher survival in patients with increased levels of autoantibodies to PDIA3. Therefore, the interplay between the presence of these antibodies and T-cell response was investigated. Peripheral blood T cells from CRC patients with high immunoglobulin G (IgG) reactivity to PDIA3 also secreted interferon gamma (IFN-γ) when stimulated in vitro with recombinant PDIA3, whereas those from CRC with low IgG reactivity to PDIA3 did not. PDIA3-pulsed dendritic cells efficiently induced proliferation and IFN-γ production of autologous CD4+ and CD8+ T cells. Finally, ex vivo analysis of tumor-infiltrating T lymphocytes from CRC patients with autoantibodies to PDIA3 revealed that PDIA3-specific Th1 effector cells accumulated in tumor tissue. These data indicate that the presence of autoantibodies to PDIA3 favors the development of an efficient and specific T-cell response against PDIA3 in CRC patients. These results may be relevant for the design of novel immunotherapeutic strategies in CRC patients.

Original languageEnglish
JournalTranslational Research
DOIs
Publication statusAccepted/In press - Aug 25 2015

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, medical
  • Public Health, Environmental and Occupational Health

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    Caorsi, C., Niccolai, E., Capello, M., Vallone, R., Chattaragada, M. S., Alushi, B., Castiglione, A., Ciccone, G., Mautino, A., Cassoni, P., De Monte, L., Álvarez-Fernández, S. M., Amedei, A., Alessio, M., & Novelli, F. (Accepted/In press). Protein disulfide isomerase A3-specific Th1 effector cells infiltrate colon cancer tissue of patients with circulating anti-protein disulfide isomerase A3 autoantibodies. Translational Research. https://doi.org/10.1016/j.trsl.2015.12.013