Abstract
IL-27 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p40-related protein subunit, EBV-induced gene 3, and a p35-related subunit, p28. IL-27 functions through IL-27R and has been shown to have potent antitumor activity via activation of a variety of cellular components, including antitumor CD8(+) T-cell responses. However, the exact mechanisms of how IL-27 enhances antitumor CD8(+) T-cell responses remain unclear. Here we show that IL-27 significantly enhances the survival of activated tumor antigen-specific CD8(+) T cells in vitro and in vivo, and programs tumor antigen-specific CD8(+) T cells into memory precursor-like effector cells, characterized by upregulation of Bcl-6, SOCS3, Sca-1, and IL-10. While STAT3 activation and the CTL survival-enhancing effects can be independent of CTL IL-10 production, we show here that IL-27-induced CTL IL-10 production contributes to memory precursor cell phenotype induction, CTL memory, and tumor rejection. Thus, IL-27 enhances antitumor CTL responses via programming tumor antigen-specific CD8(+) T cells into a unique memory precursor type of effector cells characterized by a greater survival advantage. Our results have important implications for designing immunotherapy against human cancer.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Ly / immunology
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Antigens, Ly / metabolism
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Antigens, Neoplasm / immunology*
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Antigens, Neoplasm / metabolism
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Cell Line, Tumor
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Cell Survival / immunology
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Immunologic Memory / immunology*
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Interleukin-10 / immunology*
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Interleukin-10 / metabolism
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Interleukins / immunology*
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Interleukins / metabolism
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Proto-Oncogene Proteins c-bcl-6 / immunology
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Proto-Oncogene Proteins c-bcl-6 / metabolism
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / immunology
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Suppressor of Cytokine Signaling Proteins / metabolism
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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Up-Regulation / immunology
Substances
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Antigens, Ly
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Antigens, Neoplasm
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IL10 protein, mouse
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Il27 protein, mouse
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Interleukins
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Ly6a protein, mouse
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Membrane Proteins
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Proto-Oncogene Proteins c-bcl-6
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Interleukin-10