CD4+ T cell-mediated antigen-specific immunotherapy in a mouse model of cervical cancer.
A major agenda for tumor immunology is the generation of specific immune responses leading to the destruction of incipient and frank neoplasia. In this report, we show that a novel HPV16 E7 fusion protein can produce objective therapeutic responses against incipient cervical cancer in genetically engineered mice that express in the cervix the HPV16 early region genes implicated as causative agents in human cervical cancer. Although nonresponsive toward the HPV16 E7 oncoprotein in the CD8+ T-cell compartment by virtue of MHC haplotype, the mice were capable of mounting an induced CD4+ T-cell response against E7, and in addition developed spontaneous anti-E7 antibodies. HPV16/CD4-/- mice showed increased tumor burden indicative of CD4-mediated immune surveillance. Seeking to enhance the CD4 response, we immunized mice bearing incipient cervical cancer with a recombinant protein fusing E7 with a mycobacterial heat shock protein. The incidences of cervical carcinoma and of high-grade dysplasia (CIN 3) were consequently reduced by comparison to control mice. Thus, an HPV16 E7 immunogen holds promise for noninvasive treatment and prevention of human cervical cancer.
Daniel
Dylan
D
Department of Biochemistry, Diabetes Center and Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143-0534, USA.
Chiu
Christopher
C
Giraudo
Enrico
E
Inoue
Masahiro
M
Mizzen
Lee A
LA
Chu
N Randall
NR
Hanahan
Douglas
D
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D018834:Chaperonin 60; D018833:Chaperonins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007114:Immunization; D007167:Immunotherapy; D008285:Major Histocompatibility Complex / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009163:Mycobacterium bovis / Q000235:genetics; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D010053:Ovary / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000637:transplantation / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D014765:Viral Vaccines / Q000627:therapeutic use; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000378:metabolism / Q000628:therapy
D001426:Bacterial Proteins; D018834:Chaperonin 60; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines; C074119:heat-shock protein 65, Mycobacterium; C059731:oncogene protein E7, Human papillomavirus type 16; D020780:Matrix Metalloproteinase 9; D018833:Chaperonins