title: A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination.
abstract: Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC.
authors.affiliation: Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France.|Inserm, UMR_S 911, Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Collignon
authors.affiliation: Aix-Marseille UniversiteÌ, CNRS, CRMBM, Centre de ReÌsonance MagneÌtique Biologique et MeÌdicale, UMR 7339, Marseille, France.
authors.forename: Adriana Teodora
authors.initials: AT
authors.lastname: Perles-Barbacaru
authors.affiliation: Aix-Marseille Université, VRCM, Vascular Research Center of Marseilles, Marseille, France.|Inserm, UMR_S_1076, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Robert
authors.affiliation: Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France.|Inserm, UMR_S 911, Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Silvy
authors.affiliation: Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Martinez
authors.affiliation: Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Crenon
authors.affiliation: Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France.|Inserm, UMR_S 911, Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Germain
authors.affiliation: APHM, Hôpital Nord, Laboratoire d'Anatomie-Pathologie, Marseille, France.|Aix-Marseille Université, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Garcia
authors.affiliation: Aix-Marseille UniversiteÌ, CNRS, CRMBM, Centre de ReÌsonance MagneÌtique Biologique et MeÌdicale, UMR 7339, Marseille, France.
authors.forename: Angèle
authors.initials: A
authors.lastname: Viola
authors.affiliation: Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France.|Inserm, UMR_S 911, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lombardo
authors.affiliation: Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France.|Inserm, UMR_S 911, Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Mas
authors.affiliation: Aix-Marseille Université, CRO2, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, Marseille, France.|Inserm, UMR_S 911, Marseille, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Béraud
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology; D014408:Biomarkers, Tumor / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D053804:Granzymes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D017252:CD3 Complex; D019496:Cancer Vaccines; D000939:Epitopes; D006023:Glycoproteins; D053804:Granzymes
keywords: active immunotherapy; biomarker; cancer vaccines; pancreatic cancer; tumor-associated antigen