title: Co-expression of B7-1 and ICAM-1 on tumors is required for rejection and the establishment of a memory response.
abstract: Although the transfection of B7-1 cDNA into a few mouse tumor cell lines can induce anti-tumor T cell immunity, its expression alone is ineffective in many other tumor cell lines tested. We were interested to study what factors limit B7-1 co-stimulatory activity, and decided to investigate whether B7-1 requires the cooperation of ICAM-1 to provide the minimal co-stimulatory signal for establishing an efficient anti-tumor immunity. We show that the transfection of B7-1 cDNA into three ICAM-1+ (plasmocytoma J558L, T lymphomas EL-4 and RMA), but not into two ICAM-1- tumors cell lines (adenocarcinoma TS/A and melanoma B16.F1), is sufficient to induce their complete rejection in syngeneic mice. The expression of ICAM-1 is necessary for the rejection of the B7 expressing tumors, since the primary response elicited by B7-1+ EL-4 and RMA clones expressing reduced levels of ICAM-1 is severely reduced. Furthermore, super-transfection of ICAM-1 cDNA into B7-1+ adenocarcinoma and melanoma clones optimizes their primary rejection. Histologic examination of transfected tumors reveals that B7-1 and ICAM-1 exert a potent pro-inflammatory activity. The intra-tumor infiltration is composed of both eosinophils and lymphomonocytes, and is already massive 5 days after the tumor challenge. The primary rejection of the B7-1+ ICAM-1+ tumors depends critically on CD8+ T cells, natural killer cells and granulocytes, but is independent of CD4+ T cells. Remarkably, in addition to its effects on the early phases of the immune response, the co-expression of ICAM-1 and B7-1 on tumors is also necessary for the efficient induction of a memory response. In fact, only the primary challenge with B7-1+, ICAM-1+ tumor cells protects the majority of the mice from a second injection of parental tumor cells. Collectively, our findings indicate that B7-1 and ICAM-1 are fundamental components for triggering the primary rejection of tumors and establishing a protective memory response. These findings may help to define new strategies for the rational application of co-stimulation in tumor immunotherapy.
authors.affiliation: CNR Immunogenetica e Oncologia Sperimentale, Università di Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cavallo
authors.forename: A
authors.initials: A
authors.lastname: Martin-Fontecha
authors.forename: M
authors.initials: M
authors.lastname: Bellone
authors.forename: S
authors.initials: S
authors.lastname: Heltai
authors.forename: E
authors.initials: E
authors.lastname: Gatti
authors.forename: P
authors.initials: P
authors.lastname: Tornaghi
authors.forename: M
authors.initials: M
authors.lastname: Freschi
authors.forename: G
authors.initials: G
authors.lastname: Forni
authors.forename: P
authors.initials: P
authors.lastname: Dellabona
authors.forename: G
authors.initials: G
authors.lastname: Casorati
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology*; D001483:Base Sequence; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D007156:Immunologic Memory; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation / Q000276:immunology*; D010954:Plasmacytoma / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000637:transplantation
chemical_list: D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D018799:Intercellular Adhesion Molecule-1