Abstract
Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor alpha+ (CD11b+IL-4Ralpha+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-gamma released from T lymphocytes. CD11b+IL-4Ralpha+ cells produced IL-13 and IFN-gamma and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arginase / genetics
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Arginase / metabolism
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CD11b Antigen / analysis
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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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Gene Expression / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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Immunity, Cellular / immunology
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interferon-gamma / pharmacology
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Interleukin-13 / metabolism
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Interleukin-13 / pharmacology
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Models, Immunological
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Monocytes / drug effects
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Monocytes / immunology*
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Monocytes / metabolism
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Myeloid Cells / drug effects
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Neoplasms / immunology*
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Neoplasms / metabolism
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Neoplasms / pathology
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Receptors, Cell Surface / analysis
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Spleen / cytology
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Spleen / immunology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
Substances
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CD11b Antigen
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Il4ra protein, mouse
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Interleukin-13
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Receptors, Cell Surface
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Interleukin-4
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Interferon-gamma
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Granulocyte-Macrophage Colony-Stimulating Factor
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Arginase