Signaling pathways induced by a tumor-derived vaccine in antigen presenting cells.
We have previously reported on the anti-tumoral potential of a chaperone-rich cell lysate (CRCL) vaccine. Immunization with CRCL generated from tumors elicits specific T and NK cell-dependent immune responses leading to protective immunity in numerous mouse tumor models. CRCL provides both a source of tumor antigens and danger signals leading to dendritic cell activation. In humans, tumor-derived CRCL induces dendritic cell activation and CRCL-loaded dendritic cells promote the generation of cytotoxic T lymphocytes in vitro. The current study was designed to identify the signaling events and modifications triggered by CRCL in antigen presenting cells. Our results indicate that tumor-derived CRCL not only promotes the activation of dendritic cells, but also significantly fosters the function of macrophages that thus appear as major targets of this vaccine. Activation of both cell types is associated with the induction of the MAP kinase pathway, the phosphorylation of STAT1, STAT5 and AKT and with transcription factor NF-kappaB activation in vitro and in vivo. These results thus provide important insights into the mechanisms by which CRCL-based vaccines exert their adjuvant effects on antigen presenting cells.
Cantrell
Jessica
J
Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, AZ 85724-5073, USA.
Larmonier
Claire
C
Janikashvili
Nona
N
Bustamante
Sara
S
Fraszczak
Jennifer
J
Herrell
Amanda
A
Lundeen
Tamara
T
J LaCasse
Collin
C
Situ
Elaine
E
Larmonier
Nicolas
N
Katsanis
Emmanuel
E
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D019496:Cancer Vaccines; D002457:Cell Extracts / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D051058:Oncogene Protein v-akt / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D019496:Cancer Vaccines; D002457:Cell Extracts; D016212:Transforming Growth Factor beta; D051058:Oncogene Protein v-akt