title: Comparable in vivo efficacy of CD28/B7, ICOS/GL50, and ICOS/GL50B costimulatory pathways in murine tumor models: IFNgamma-dependent enhancement of CTL priming, effector functions, and tumor specific memory CTL.
abstract: Increasing evidence suggests that B7/CD28 interactions are important in clonal expansion and effector function of nai;ve CD4(+) T cells, whereas ICOS/GL50 interactions may optimize the responses of recently activated T(H) cells. In tumor models, it has been shown that engagement of ICOS, like CD28, by its ligands can be effective in enhancing tumor immunity. In this report, we have directly compared the in vivo efficacy of CD28 vs ICOS activation in the MethA fibrosarcoma and B16F1 melanoma tumor models. We studied the efficacy of systemic treatment of tumors with murine B7.2-IgG or GL50-IgG fusion proteins, and the therapeutic potential of B7.1 or GL50 vaccines given during various phases of the antitumor responses. In addition, we compare the efficacy of ICOS-ligand splice variants GL50 and GL50B in promoting tumor immunity. We find that each of these pathways is equally effective in promoting tumor immunity and that the efficacy of both GL50 and B7.1 vaccines is IFN-gamma but not IL-10 dependent. Our results suggest that CD28 or ICOS costimulation-based strategies may be equally efficacious as adjuvants to conventional cancer treatment.
authors.affiliation: Wyeth Research, 200 Cambridgepark Drive, Cambridge, MA 02140, USA.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Zuberek
authors.forename: Vincent
authors.initials: V
authors.lastname: Ling
authors.forename: Paul
authors.initials: P
authors.lastname: Wu
authors.forename: Hak-Ling
authors.initials: HL
authors.lastname: Ma
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Mary
authors.initials: M
authors.lastname: Collins
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Dunussi-Joannopoulos
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000276:immunology* / Q000627:therapeutic use; D018106:CD28 Antigens / Q000276:immunology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D011506:Proteins / Q000276:immunology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D018106:CD28 Antigens; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011506:Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma