T cell activation by heat shock protein 70 vaccine requires TLR signaling and scavenger receptor expressed by endothelial cells-1.
Heat shock protein (HSP) 70 isolated from tumor-dendritic cell (DC) fusions (HSP70.PC-F) induces potent antitumor immunity and prevents growth of such tumors. In the present study, we have examined mechanisms underlying such antitumor activity of the HSP70.PC-F vaccine. The degree of antitumor immunity induced by HSP70.PC-F depended on intact TLR signaling in immunized animals, and mice in which the tlr2 and tlr4 genes were both inactivated did not respond to the vaccine. The reduced responses to HSP70.PC-F vaccine in such tlr knockout mice were restored by immunization of animals with HSP70.PC-F-pulsed wild-type DC, indicating a key role for this cell type in HSP70.PC-F-mediated immunity. Our studies also indicate a role for the scavenger receptor expressed by endothelial cells-1 (SREC-1) in antitumor immunity induced by HSP70.PC-F. These two receptor types appeared functionally interdependent, as indicated by the finding that tlr2 and tlr4 knockout decreases HSP70 binding in double-knockout DC and reduces SREC-1 expression. In addition, TLR-dependent, tumor cell killing was suppressed by SREC-1 knockdown in DC, suggesting a significant role for this receptor in HSP70.PC-F-mediated tumor immunity.
Gong
Jianlin
J
Center for the Molecular Stress Response, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA. jgong@bu.edu
Zhu
Bangmin
B
Murshid
Ayesha
A
Adachi
Hideki
H
Song
Baizheng
B
Lee
Allegra
A
Liu
Chunlei
C
Calderwood
Stuart K
SK
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D051128:Scavenger Receptors, Class F / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; D051128:Scavenger Receptors, Class F; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4