title: Protein disulfide isomerase A3-specific Th1 effector cells infiltrate colon cancer tissue of patients with circulating anti-protein disulfide isomerase A3 autoantibodies.
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.
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Caorsi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Niccolai
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Capello
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Vallone
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Chattaragada
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Brunilda
authors.initials: B
authors.lastname: Alushi
authors.affiliation: SCDU Epidemiologia dei Tumori-CPO Piemonte, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Castiglione
authors.affiliation: SCDU Epidemiologia dei Tumori-CPO Piemonte, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Ciccone
authors.affiliation: BioClarma, Molecular Biotechnology Centre, Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mautino
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cassoni
authors.affiliation: Tumor Immunology Unit, IRCCS-San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: De Monte
authors.affiliation: Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Álvarez-Fernández
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), Florence, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Amedei
authors.affiliation: Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Alessio
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy; Molecular Biotechnology Center, University of Turin, Turin, Italy. Electronic address: franco.novelli@unito.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000097:blood*; D003110:Colonic Neoplasms / Q000097:blood* / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human