Abstract
The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20-55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host's tumor-specific CD4+ T cells. The identification of OX-40R+ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.
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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Adjuvants, Immunologic / administration & dosage
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Adjuvants, Immunologic / metabolism
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Animals
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Breast Neoplasms / immunology
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Breast Neoplasms / pathology
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Cancer Vaccines / administration & dosage
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Cancer Vaccines / immunology*
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Cancer Vaccines / metabolism*
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / prevention & control
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Female
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Humans
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Ligands
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Mammary Neoplasms, Experimental / immunology
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Mammary Neoplasms, Experimental / prevention & control
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Melanoma, Experimental / immunology
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Melanoma, Experimental / prevention & control
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Neoplasm Transplantation
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Receptors, Immunologic / administration & dosage
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Receptors, Immunologic / immunology*
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Receptors, Immunologic / metabolism*
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Receptors, OX40
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Receptors, Tumor Necrosis Factor*
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Sarcoma, Experimental / immunology
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Sarcoma, Experimental / prevention & control
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / administration & dosage
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / biosynthesis
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology*
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism*
Substances
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Adjuvants, Immunologic
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Cancer Vaccines
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Ligands
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Receptors, Immunologic
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Receptors, OX40
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Receptors, Tumor Necrosis Factor
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TNFRSF4 protein, human
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Tnfrsf4 protein, mouse
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Tumor Necrosis Factor Receptor Superfamily, Member 7