title: GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression.
abstract: In chemical carcinogenesis models, GRP94 (gp96) elicits tumor-specific protective immunity. The tumor specificity of this response is thought to reflect immune responses to GRP94-bound peptide antigens, the cohort of which uniquely identifies the GRP94 tissue of origin. In this study, we examined the apparent tissue restriction of GRP94-elicited protective immunity in a 4T1 mammary carcinoma model. We report that the vaccination of BALB/c mice with irradiated fibroblasts expressing a secretory form of GRP94 markedly suppressed 4T1 tumor growth and metastasis. In addition, vaccination with irradiated cells secreting the GRP94 NH(2)-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression. Conditioned media from cultures of GRP94 or GRP94 NTD-secreting fibroblasts elicited the up-regulation of major histocompatibility complex class II and CD86 in dendritic cell cultures, consistent with a natural adjuvant function for GRP94 and the GRP94 NTD. Based on these findings, we propose that GRP94-elicited tumor suppression can occur independent of the GRP94 tissue of origin and suggest a primary role for GRP4 natural adjuvant function in antitumor immune responses.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, 366 Nanaline H. Duke, Durham, NC 27710, USA.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Baker-LePain
authors.forename: Marcella
authors.initials: M
authors.lastname: Sarzotti
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Fields
authors.forename: Chuan-Yuan
authors.initials: CY
authors.lastname: Li
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Nicchitta
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D051940:B7-2 Antigen; D016227:Benzoquinones; D001665:Binding Sites; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology*; D011809:Quinones / Q000378:metabolism*; D014611:Vaccination
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051940:B7-2 Antigen; D016227:Benzoquinones; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins; D011809:Quinones; C052646:sarcoma glycoprotein gp96 rejection antigens; C001277:geldanamycin