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

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• 作者：Cristiana Caorsi^a ; ^b ; Elena Niccolai^c ; ^d ; Michela Capello^a ; ^e ; Rosario Vallone^a ; Michelle S. Chattaragada^a ; ^e ; Brunilda Alushi^a ; Anna Castiglione^f ; Gianni Ciccone^f ; Alessandro Mautino^g ; Paola Cassoni^h ; Lucia De Monteⁱ ; Sheila M. Á ; lvarez-Ferná ; ndez^j ; Amedeo Amedei^c ; ^d ; Massimo Alessio^j ; Francesco Novelli^a ; ^b ; ^e ; ^k ; ^{franco.novelli@unito.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CRC ; colorectal cancer ; TAAs ; tumor-associated antigens ; IgG ; immunolgobulin G ; PDIA3 ; protein disulfide isomerase A3 ; HSs ; healthy subjects ; Tcc ; T-cell clones ; SD ; standard deviation ; DC ; dendritic cell ; PBMCs ; peripheral blood mononuclear cells ; IFN-γ ; interferon gamma ; HLA ; human leukocyte antigen ; TILs ; tumor-infiltrating lymphocytes ; MHC ; major histocompatibility complex
• 刊名：Translational Research
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：171
• 期：Complete
• 页码：17-28.e2
• 全文大小：779 K

文摘

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.