Abstract
We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8(+) and NK1.1(+) cells but occurred irrespective of the presence of CD4(+) T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Adjuvants, Immunologic / therapeutic use
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Animals
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Antibodies, Monoclonal / therapeutic use
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Antigens / immunology
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Antigens, CD
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Antigens, Differentiation / biosynthesis*
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Antigens, Differentiation / immunology
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Antigens, Ly
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Antigens, Surface
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Antineoplastic Combined Chemotherapy Protocols / immunology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Autoimmune Diseases / immunology*
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Autoimmune Diseases / therapy
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CD8-Positive T-Lymphocytes / immunology
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CTLA-4 Antigen
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Cancer Vaccines / immunology*
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Cancer Vaccines / therapeutic use
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Cell Survival / immunology
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Female
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Graft Rejection / immunology*
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Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis*
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Granulocyte-Macrophage Colony-Stimulating Factor / immunology
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Hair Color / immunology
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Immunoconjugates*
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Immunosuppressive Agents / therapeutic use
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Injections, Subcutaneous
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Lectins, C-Type
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Lung Neoplasms / immunology
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Lung Neoplasms / pathology
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Lung Neoplasms / secondary
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Lymphocyte Activation
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Melanoma, Experimental / immunology*
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Melanoma, Experimental / therapy
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Mice
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Mice, Inbred C57BL
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NK Cell Lectin-Like Receptor Subfamily B
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Neoplasm Transplantation
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Proteins / immunology
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Skin Pigmentation / immunology
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T-Lymphocytes, Cytotoxic / immunology*
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Vitiligo / immunology*
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Vitiligo / pathology
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Vitiligo / therapy
Substances
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Adjuvants, Immunologic
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Antibodies, Monoclonal
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Antigens
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Antigens, CD
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Antigens, Differentiation
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Antigens, Ly
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Antigens, Surface
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CTLA-4 Antigen
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Cancer Vaccines
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Ctla4 protein, mouse
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Immunoconjugates
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Immunosuppressive Agents
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Klrb1c protein, mouse
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Lectins, C-Type
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NK Cell Lectin-Like Receptor Subfamily B
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Proteins
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Abatacept
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Granulocyte-Macrophage Colony-Stimulating Factor