Exosomes harbor B cell targets in pancreatic adenocarcinoma and exert decoy function against complement-mediated cytotoxicity

• Published in: Nature communications Vol. 10; no. 1; pp. 254 - 13
• Main Authors: Capello, Michela, Vykoukal, Jody V., Katayama, Hiroyuki, Bantis, Leonidas E., Wang, Hong, Kundnani, Deepali L., Aguilar-Bonavides, Clemente, Aguilar, Mitzi, Tripathi, Satyendra C., Dhillon, Dilsher S., Momin, Amin A., Peters, Haley, Katz, Matthew H., Alvarez, Hector, Bernard, Vincent, Ferri-Borgogno, Sammy, Brand, Randall, Adler, Douglas G., Firpo, Matthew A., Mulvihill, Sean J., Molldrem, Jeffrey J., Feng, Ziding, Taguchi, Ayumu, Maitra, Anirban, Hanash, Samir M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 147/28; 631/61/475; 631/67/1504/1713; 631/67/580; 82/58; 96/31; Adenocarcinoma; Aged; Aged, 80 and over; Antibody Formation - immunology; Antibody response; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Autoantibodies; Autoantibodies - immunology; B-Lymphocytes - immunology; Beta cells; Cancer; Carcinoma, Pancreatic Ductal - blood; Carcinoma, Pancreatic Ductal - immunology; Cell Line, Tumor; Cohort Studies; Complement; Complement system; Complement System Proteins - immunology; Cytotoxicity; Datasets as Topic; Exosomes; Exosomes - immunology; Exosomes - metabolism; Exosomes - ultrastructure; Female; Gene Expression Profiling; Healthy Volunteers; Humanities and Social Sciences; Humans; Immune response; Immune response (humoral); Immune system; Immunoglobulins; Male; Microscopy, Electron; Middle Aged; multidisciplinary; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - blood; Pancreatic Neoplasms - immunology; Plasmas (physics); Proteins; Proteomics - methods; Science; Science (multidisciplinary); Sequence Analysis, RNA; Toxicity; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-08109-6

Although B cell response is frequently found in cancer, there is little evidence that it alters tumor development or progression. The process through which tumor-associated antigens trigger humoral response is not well delineated. We investigate the repertoire of antigens associated with humoral immune response in pancreatic ductal adenocarcinoma (PDAC) using in-depth proteomic profiling of immunoglobulin-bound proteins from PDAC patient plasmas and identify tumor antigens that induce antibody response together with exosome hallmark proteins. Additional profiling of PDAC cell-derived exosomes reveals significant overlap in their protein content with immunoglobulin-bound proteins in PDAC plasmas, and significant autoantibody reactivity is observed between PDAC cell-derived exosomes and patient plasmas compared to healthy controls. Importantly, PDAC-derived exosomes induce a dose-dependent inhibition of PDAC serum-mediated complement-dependent cytotoxicity towards cancer cells. In summary, we provide evidence that exosomes display a large repertoire of tumor antigens that induce autoantibodies and exert a decoy function against complement-mediated cytotoxicity. The humoral immune response role in cancer is unclear. Here the authors perform an in-depth proteomic profiling of immunoglobulin-bound proteins in plasma from pancreatic ductal adenocarcinoma patients and find cancer-cell specific antibodies neutralized by binding to cancer-cell derived exosomes.