title: Enhancing CTL responses to melanoma cell vaccines in vivo: synergistic increases obtained using IFNgamma primed and IFNbeta treated B7-1+ B16-F10 melanoma cells.
abstract: Sequentially treating human melanoma cell lines by priming with interferon-gamma before adding interferon-beta was previously found to be the most efficient protocol for producing concurrently increased expression of the three surface antigens B7-1, intercellular adhesion molecule-1 and human histocompatibility leucocyte antigens Class I. The present study describes similar outcomes when the same sequential intercellular adhesion molecule-based protocol is applied to murine B16-F10 melanoma cells as well as preclinical studies using the B16-F10 model as a poorly immunogenic melanoma. Thus, treating B16-F10 cells or a highly expressing B7-1 transfected subline (B16-F10/B7-1 hi) by priming with interferon-gamma for 24 h before adding interferon-beta for a further 48 h (interferon-gamma 72/beta 48) increased expression of all three surface antigens, particularly major histocompatibility complex class I whose increased expression was sustained for several days. As a whole tumour cell vaccine, interferon-gamma 72/beta 48 treated B16-F10 cells produced greater levels of cytoxic T lymphocyte response compared to vaccines prepared from cells treated with a single type of interferon. Furthermore, B16-F10 cells expressing high levels of B7-1 and treated using the interferon-gamma 72/beta 48 protocol (interferon-gamma 72/beta 48-treated B16-F10/B7-1 hi) produced substantially increased cytoxic T lymphocyte responses with a fivefold greater synergy than the combined results of either interferon treated or B7-1 expressing cells tested individually. The resulting CD8+ cytoxic T lymphocyte showed greater specificity for B16-F10 cells with tenfold higher killing than for syngeneic EL-4 lymphoma cells. Killing proceeded via the perforin-mediated pathway. CTL responses were induced independent of CD4+ T helper cells. The majority of mice receiving interferon-gamma 72/beta 48-treated B16-F10/B7-1 hi vaccine in vivo remained tumour free after challenge with 5 x 105 live B16-F10 cells expressing intermediate B7-1 levels. The novel strategy described will help enhance vaccine potency when applied clinically to prepare whole cell based cancer vaccine therapies.
authors.affiliation: Department Biochemistry and Molecular Biology, School of Biomedical Science, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Shala
authors.initials: S
authors.lastname: Dezfouli
authors.forename: Irene
authors.initials: I
authors.lastname: Hatzinisiriou
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002460:Cell Line; D004195:Disease Models, Animal; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016899:Interferon-beta / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D011956:Receptors, Cell Surface; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta; D007371:Interferon-gamma