Costimulation of tumor-reactive CD4+ and CD8+ T lymphocytes by B7, a natural ligand for CD28, can be used to treat established mouse melanoma.
Interactions between the costimulatory molecule B7 on APC and its counter-receptor CD28 on T lymphocytes play a key role in the induction of cell-mediated immune responses. We studied the role of costimulation of tumor-reactive T cells by B7 in the immune destruction of the K1735-M2 mouse melanoma into which the gene encoding the human melanoma-associated Ag, p97, had been transfected. Previous work has demonstrated that the p97 transfectant cl62 is immunogenic but still grows progressively in immunocompetent C3H/HeN mice and that adoptive transfer of p97-specific CD4+ T cells can induce the regression of small established cl62 tumors metastatic to the lungs. We have now shown that expression of B7 in cl62 after retroviral-mediated gene transfer eliminated its ability to grow in immunocompetent mice but not in T cell-deficient nude mice. Mice immunized with B7-transduced p97+ cells had an increased activity of both CD4+ T cells, which could proliferate in response to the p97 Ag, and CD8+ CTL, which could lyse a broad spectrum of cultured syngeneic p97+ and p97- tumor lines but not allogeneic tumor lines or syngeneic lymphoblasts. Both CD4+ and CD8+ T cell subsets were required for tumor rejection, and the depletion of CD4+ T cells in vivo decreased the tumoricidal activity of CD8+ CTL. Treatment of mice bearing an 8-day established s.c. cl62 melanoma by i.p. injection of B7+ cells from 2A, a highly immunogenic p97 transfectant, resulted in complete tumor regression and cure, injection of B7- 2A cells did not. The therapeutic effect was specific for the cl62 tumor. Our results demonstrate that costimulation by B7 can amplify both CD4+ and CD8+ T cell responses against small tumors toward therapeutic benefit.
Li
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Y
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
McGowan
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P
Hellström
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Hellström
K E
KE
Chen
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L
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis; D000954:Antigens, Surface / Q000032:analysis; D018122:B7-1 Antigen / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis; D003602:Cytotoxicity, Immunologic; D005260:Female; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D018122:B7-1 Antigen; D018106:CD28 Antigens; D016827:CD8 Antigens; D008024:Ligands