title: Pancreatic cancer immunotherapy using a tumor lysate vaccine, engineered to express α-gal epitopes, targets pancreatic cancer stem cells.
abstract: Pancreatic cancer is a lethal disease that remains one of the most resistant to traditional therapies. Immunotherapy in pancreatic cancer induces the recruitment and activation of T cells that recognize tumor-associated antigens (TAAs); thus, the mechanism differs from that of chemotherapy and radiotherapy. The goal of cancer immunotherapy is to elicit immune responses against autologous tumors, and especially to induce multiple T cell clones against a variety of TAAs. In the present study, we prepared a polyvalent tumor lysate vaccine engineered to express the α-gal epitopes, Galα1-3Galβ1-4 GlcNAc-R (i.e., α-gal tumor lysate), from primary tumors. The vaccine elicited strong antibody production against multiple TAAs in pancreatic cancer cells and induced activation of multiple tumor-specific T cells in α1,3-galactosyltransferase (α1,3GT) knockout (KO) mice. The tumor lysate vaccine exhibited a similar effect on pancreatic cancer stem cells (CSCs) with the CD44+CD24+ phenotype. Furthermore, in vivo experiments using NOD/SCID mice, inoculated with splenocytes from KO mice vaccinated with the α-gal tumor lysate and injected with pancreatic cancer cells, showed successful induction of a marked immune response that resulted in suppression of tumorigenesis and significant improvement in overall survival. In contrast, inoculation of lymphocytes from KO mice vaccinated with control tumor lysate vaccine had no effects on tumor growth and survival. The results of both in vitro and in vivo experiments emphasize the efficiency of tumor lysate vaccines expressing α-gal epitopes in targeting all pancreatic cancer cells, including differentiated cancer cells and pancreatic CSCs. The α-gal tumor lysate vaccine could be the basis for a novel therapeutic approach in human clinical trials.
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Tanida
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanemura
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Miyoshi
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nonaka
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akita
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hama
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000138:chemical synthesis*; D002457:Cell Extracts / Q000276:immunology / Q000627:therapeutic use*; D000939:Epitopes / Q000276:immunology*; D005818:Genetic Engineering / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured; D000519:alpha-Galactosidase / Q000235:genetics / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D002457:Cell Extracts; D000939:Epitopes; D000519:alpha-Galactosidase