title: STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells.
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.
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, 15 rue de l'Ecole de Médecine, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, 15 rue de l'Ecole de Médecine, Paris, France. Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France. Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France. Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Yang
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France. Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, 15 rue de l'Ecole de Médecine, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, 15 rue de l'Ecole de Médecine, Paris, France. Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France. Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France. University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Pietrocola
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, 15 rue de l'Ecole de Médecine, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, 15 rue de l'Ecole de Médecine, Paris, France. Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France. Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France. University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France. Institut National de la Santé Et de la Recherche Medicale (INSERM), U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France. University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, 15 rue de l'Ecole de Médecine, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, 15 rue de l'Ecole de Médecine, Paris, France. Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France. Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France. Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China. kroemer@orange.fr yuting.ma@crc.jussieu.fr.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, 15 rue de l'Ecole de Médecine, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, 15 rue de l'Ecole de Médecine, Paris, France. Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France. Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, Villejuif, France. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. Department of Women's and Children's Health, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden. kroemer@orange.fr yuting.ma@crc.jussieu.fr.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics; D054370:Chemokine CXCL9 / Q000096:biosynthesis* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007121:Immunocompetence; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015533:Transcriptional Activation
chemical_list: D000903:Antibiotics, Antineoplastic; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D003499:Cyclic S-Oxides; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D009363:Neoplasm Proteins; D054367:Receptors, CXCR3; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C517409:stattic; D053633:Receptor, Interferon alpha-beta; D004317:Doxorubicin