title: Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells.
abstract: The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy. Our results define a pathogenic role for IL34 in mediating immunosuppression and chemoresistance and identify it as a tractable target for anticancer therapy. Cancer Res; 76(20); 6030-42. ©2016 AACR.
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baghdadi
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Wada
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nakanishi
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Abe
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Nanumi
authors.initials: N
authors.lastname: Han
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Wira Eka
authors.initials: WE
authors.lastname: Putra
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Endo
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Hidemichi
authors.initials: H
authors.lastname: Watari
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sakuragi
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hida
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kichizo
authors.initials: K
authors.lastname: Kaga
authors.affiliation: Molecular Pathology and Genetics Division, Kanagawa Cancer Center, Yokohama, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyagi
authors.affiliation: Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yokose
authors.affiliation: Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu, Japan. Center for Antibody and Vaccine, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takano
authors.affiliation: Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu, Japan. Center for Antibody and Vaccine, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. seino@igm.hokudai.ac.jp.
authors.forename: Ken-Ichiro
authors.initials: KI
authors.lastname: Seino
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016764:Cell Polarity; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007108:Immune Tolerance; D007378:Interleukins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000502:physiology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C000604004:Csf1r protein, mouse; C529076:IL34 protein, human; D007378:Interleukins; D016328:NF-kappa B; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt