Secretion of stress protein grp170 promotes immune-mediated inhibition of murine prostate tumor.
It is well established that certain stress proteins or molecular chaperones are highly efficient in cross-presenting tumor-derived antigens, resulting in a potent antitumor immune response. In this study we demonstrate that genetic modification of weakly immunogenic murine prostate tumor cells (TRAMP-C2) by stable transfection with a secretable form of endoplasmic reticulum resident chaperone grp170 significantly enhances its immunogenicity in vivo. Generation of systemic antitumor immunity is indicated by the growth suppression of distant parental tumors, which is associated with increased tumor infiltration, elevated effector functions of CD8(+) T-cells. Immunization with inactivated grp170-secreting C2 cells augments a CD8(+) T-cell dependent, tumor-protective effect. Furthermore, infection of C2 tumor cells with a nonreplicating adenoviral vectors encoding secretable grp170 promotes tumor immunogenicity more effectively than plasmid transduction, as shown by the increased production of pro-inflammatory cytokine TNF-alpha by dendritice cells and enhanced therapeutic efficacy in treating pre-established tumors. Given a repertoire of undefined antigens in prostate tumor, manipulation of cellular compartmentalization of immuno-stimulatory chaperone grp170 to elicit systemic tumor immunity may be used to improve treatment outcomes for prostate cancer when combined with other treatment modalities.
Gao
Ping
P
Department of Cellular Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Sun
Xiaolei
X
Chen
Xing
X
Subjeck
John
J
Wang
Xiang-Yang
XY
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006023:Glycoproteins / Q000276:immunology* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D019496:Cancer Vaccines; D006023:Glycoproteins; D018840:HSP70 Heat-Shock Proteins; C098410:glucose-regulated protein 170