Induction of CD4-independent E7-specific CD8+ memory response by heat shock fusion protein.
Infection with human papillomavirus type 16 (HPV16) is strongly associated with a number of disease states, of which cervical and anal cancers represent the most drastic endpoints. Induction of T-cell-mediated immunity, particularly cytotoxic T lymphocytes (CTL), is important in eradication of HPV-induced lesions. Studies have shown that heat shock protein fusion proteins are capable of inducing potent antigen-specific CTL activity in experimental animal models. In addition, E7-expressing tumors in C57BL/6 mice can be eradicated by treatment with HspE7, an Hsp fusion protein composed of Mycobacterium bovis BCG Hsp65 linked to E7 protein of HPV16. More importantly, HspE7 has also displayed significant clinical benefit in phase II clinical trials for the immunotherapy of HPV-related diseases. To delineate the mechanisms underlying the therapeutic effects of HspE7, we investigated the capability of HspE7 to induce antigen-specific protective immunity. Here, we demonstrate that HspE7 primes potent E7-specific CD8(+) T cells with cytolytic and cytokine secretion activities. These CD8(+) T cells can differentiate into memory T cells with effector functions in the absence of CD4(+) T-cell help. The HspE7-induced memory CD8(+) T cells persist for at least 17 weeks and confer protection against E7-positive murine tumor cell challenge. These results indicate that HspE7 is a promising immunotherapeutic agent for treating HPV-related disease. Moreover, the ability of HspE7 to induce memory CD8(+) T cells in the absence of CD4(+) help indicates that HspE7 fusion protein may have activity in individuals with compromised CD4(+) functions, such as those with invasive cancer and/or human immunodeficiency virus infection.
Liu
Hongwei
H
Nventa Biopharmaceuticals Corporation, Victoria, BC, Canada V8Z 4B9.
Wu
Bill H
BH
Rowse
Gerry J
GJ
Emtage
Peter C R
PC
D000818:Animals; D000970:Antineoplastic Agents; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D018834:Chaperonin 60; D018833:Chaperonins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000517:prevention & control; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014412:Tumor Virus Infections / Q000517:prevention & control
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D015704:CD4 Antigens; D018834:Chaperonin 60; D016207:Cytokines; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; C074119:heat-shock protein 65, Mycobacterium; C059731:oncogene protein E7, Human papillomavirus type 16; D018833:Chaperonins