title: Tumor-derived, chaperone-rich cell lysate activates dendritic cells and elicits potent antitumor immunity.
abstract: We have utilized a free-solution isoelectric focusing technique (FS-IEF) to obtain chaperone-rich cell lysate (CRCL) fractions from clarified tumor homogenates and have previously reported on their vaccinating potential. To better understand the underlying mechanisms as well as to improve on the immunizing efficacy of tumor-derived chaperone complexes, in the present study we examined the effects of CRCL-loaded dendritic cells (DCs) against 12B1, an aggressive bcr-abl+ murine leukemia tumor. We found that DCs incubated with 12B1-derived CRCL had higher expression of CD40 and major histocompatibility complex class II (MHC-II) on their cell surface, produced more interleukin-12 (IL-12), and had superior immunostimulatory capacity in a mixed leukocyte reaction (MLR) when compared with DCs exposed to unfractionated tumor lysate or purified heat-shock protein 70 (HSP70). Vaccination of mice with 12B1 CRCL-pulsed DCs significantly prolonged their survival, with more than 80% of mice rejecting their tumors following a lethal challenge with live 12B1 compared with those immunized with tumor lysate or HSP70-loaded DCs. The protective immunity generated was tumor specific, long lasting, and both CD4+ and CD8+ T-cell dependent. Moreover, immunization with CRCL-loaded DCs resulted in a 75% cure rate in mice with pre-existing 12B1 tumors. Our findings indicate that CRCL has prominent adjuvant effects and is a very effective source of tumor antigen for pulsing DCs. FS-IEF-derived CRCL-pulsed DCs are a promising anticancer vaccine that warrants clinical research and development.
authors.affiliation: Department of Pediatrics, University of Arizona, Tucson, AZ 85724-5073, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.forename: Hanping
authors.initials: H
authors.lastname: Feng
authors.forename: Michael W
authors.initials: MW
authors.lastname: Graner
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Katsanis
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis; D002474:Cell-Free System / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018664:Interleukin-12 / Q000096:biosynthesis; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II; D018832:Molecular Chaperones; D018664:Interleukin-12