Abstract
Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy.
Keywords:
Anti-OX40 Ab; CD8; CpG ODN; IL-4; Macrophages.
MeSH terms
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Animals
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Antibodies, Neutralizing / immunology
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Antibodies, Neutralizing / pharmacology*
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / immunology
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Immunotherapy / methods*
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Interleukin-4 / antagonists & inhibitors*
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Interleukin-4 / genetics
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Interleukin-4 / immunology
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Macrophages / classification
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Macrophages / drug effects
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Macrophages / immunology
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Mice, Inbred BALB C
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Neoplasms, Experimental / immunology
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Neoplasms, Experimental / pathology
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Neoplasms, Experimental / therapy*
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Oligodeoxyribonucleotides / immunology
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Oligodeoxyribonucleotides / pharmacology
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Receptors, OX40 / antagonists & inhibitors
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Receptors, OX40 / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes, Cytotoxic / drug effects
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T-Lymphocytes, Cytotoxic / immunology
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Time Factors
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Treatment Outcome
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Tumor Burden / drug effects
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Tumor Burden / genetics
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Tumor Burden / immunology
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Tumor Microenvironment / drug effects*
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Tumor Microenvironment / immunology
Substances
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Antibodies, Neutralizing
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CPG-oligonucleotide
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Oligodeoxyribonucleotides
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Receptors, OX40
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Interleukin-4