Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection.
This study elucidates a basically new mechanism of function of a virus-modified tumor cell vaccine which has been successful in mouse tumor models (metastatic ESb lymphoma and B16-F10 melanoma) in preventing or delaying metastatic spread and improving survival and which is being tested in clinical studies. Modification of tumor cells by a low dose of Newcastle disease virus (NDV), which caused this therapy effect, led to an augmentation of the tumor-specific cytotoxic CD8 T-cell (CTL) response and to increased CD4 T-helper activity in the absence of an antiviral T-cell response. When various noninfectious NDV preparations, which, according to newly established quantitative tests, had lost one or several of the viral functions, were tested, noninfectious virus particles with inactive fusion proteins and virus inactivated by UV light, which could fuse but could not replicate, were as active as infectious NDV in the tumor-specific CTL response. In contrast, NDV inactivated by heat treatment (NDV-HI) had no effect on the CTL response. NDV-HI, even when added to the cultures in excess, did not modulate the antitumor CTL response, which argues against a nonspecific adjuvant effect. There was no mitogenic effect of NDV. Because NDV-HI was not able to bind to the tumor cell surface and because hemagglutinin-neuraminidase c-DNA transfectants increased antigen-presenting function as virus-modified cells do, we propose that the NDV effect in the CTL response is caused by the introduction of functional viral hemagglutinin-neuraminidase molecules (1000 per virus particle) into the tumor cell surface, thereby facilitating cell-cell interactions through their cell-binding and neuraminidase activity.
Schirrmacher
V
V
German Cancer Research Center, Division of Cellular Immunology, 0710, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Haas
C
C
Bonifer
R
R
Ertel
C
C
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D015707:HN Protein / Q000032:analysis / Q000276:immunology; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018448:Models, Immunological; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009522:Newcastle disease virus / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D015707:HN Protein; D011994:Recombinant Proteins