Fusion proteins of Hsp70 with tumor-associated antigen acting as a potent tumor vaccine and the C-terminal peptide-binding domain of Hsp70 being essential in inducing antigen-independent anti-tumor response in vivo.
Hsp70s are a family of ATP-dependent chaperones of relative molecular mass around 70 kDa. Immunization of mice with Hsp70 isolated from tumor tissues has been proved to elicit specific protective immunity against the original tumor challenge. In this work, we investigated whether Hsp70 can be used as vehicle to elicit immune response to its covalence-accompanying antigen. A recombinant protein expression vector was constructed that permitted the production of recombinant protein fusing tumor-associated antigen (eg, Mela) to the C terminus of Hsp70. We found that the Hsp70-Mela fusion protein can elicit strong cellular immune responses against murine tumor B16, which expresses protein Mela. The Hsp70 peptide-binding domain deletion mutant of the fusion protein was sufficient for inducing Mela-specific cytotoxic T lymphocyte but was not sufficient for engendering potent anti-tumor immunity against B16. We also found that host natural killer (NK) cells were stimulated in vivo by C-terminal domain of Hsp70. We thus presume that Hsp70 fusion proteins suppress tumor growth via at least 2 distinct pathways: one is covalence-accompanying antigen dependent; another is antigen independent. The C-terminal domain of Hsp70 seemed to be the crucial part in eliciting antigen-independent responses, including NK cell stimulation, against tumor challenges. Furthermore, we found that immunization with multiple Hsp70 fusion proteins resulted in a better anti-tumor effect.
Zhang
Honghai
H
Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China.
Huang
Weida
W
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D004926:Escherichia coli / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008979:Moloney murine leukemia virus / Q000502:physiology; D009368:Neoplasm Transplantation / Q000473:pathology; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA