Abstract
STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3(-/-) cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell-dependent and T lymphocyte-mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3(-/-) cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3(Y705F)) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3(-/-) cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3(-/-) and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells.
©2015 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / administration & dosage
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Antibiotics, Antineoplastic / pharmacology
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Antibiotics, Antineoplastic / therapeutic use*
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Cell Line, Tumor
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Chemokine CXCL10 / biosynthesis*
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Chemokine CXCL10 / genetics
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Chemokine CXCL9 / biosynthesis*
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Chemokine CXCL9 / genetics
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Colorectal Neoplasms / drug therapy
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / therapy*
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Combined Modality Therapy
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Cyclic S-Oxides / administration & dosage
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Cyclic S-Oxides / pharmacology
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Cyclic S-Oxides / therapeutic use*
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Dendritic Cells / immunology
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Doxorubicin / administration & dosage
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Doxorubicin / pharmacology
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Doxorubicin / therapeutic use*
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Drug Synergism
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Female
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Fibrosarcoma / drug therapy
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Fibrosarcoma / immunology
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Fibrosarcoma / therapy*
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Gene Expression Regulation, Neoplastic / drug effects*
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Immunocompetence*
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Interferon Type I / biosynthesis*
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Interferon Type I / genetics
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Lymphocytes, Tumor-Infiltrating / 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, Nude
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Receptor, Interferon alpha-beta / antagonists & inhibitors
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Receptors, CXCR3 / antagonists & inhibitors
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Receptors, CXCR3 / physiology
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STAT3 Transcription Factor / antagonists & inhibitors*
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / physiology
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Signal Transduction / drug effects
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T-Lymphocytes, Cytotoxic / immunology
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Transcriptional Activation
Substances
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Antibiotics, Antineoplastic
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Chemokine CXCL10
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Chemokine CXCL9
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Cxcl10 protein, mouse
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Cxcl9 protein, mouse
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Cxcr3 protein, mouse
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Cyclic S-Oxides
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Ifnar1 protein, mouse
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Interferon Type I
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Neoplasm Proteins
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Receptors, CXCR3
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STAT3 Transcription Factor
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Stat3 protein, mouse
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stattic
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Receptor, Interferon alpha-beta
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Doxorubicin