title: Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma.
abstract: Neuroblastoma is the most common extracranial solid cancer type in childhood, and high-risk patients have poor prognosis despite aggressive multimodal treatment. Neuroblastoma-driven inflammation contributes to the induction of suppressive myeloid cells that hamper efficient antitumor immune responses. Therefore, we sought to enhance antitumor immunity by removing immunosuppression mediated by myeloid cells.
  
  
  
  The prognostic values of myeloid cells are demonstrated by analyzing genomic datasets of neuroblastoma patients. The impact of tumor-derived factors on myelopoiesis and local induction of suppressive myeloid cells is dissected by in vitro culture models using freshly isolated human CD34(+) hematopoietic stem cells, primary human monocytes, and murine bone marrow cells. To test the therapeutic efficacy of BLZ945 as a monotherapy or in combination with checkpoint inhibitors, we used a transgenic murine model (TH-MYCN) that develops aggressive spontaneous neuroblastoma.
  
  
  
  We report that infiltrating CSF-1R(+) myeloid cells predict poor clinical outcome in patients with neuroblastoma. In vitro, neuroblastoma-derived factors interfere with early development of myeloid cells and enable suppressive functions on human monocytes through M-CSF/CSF-1R interaction. In a transgenic mouse model (TH-MYCN) resembling high-risk human neuroblastoma, antagonizing CSF-1R with a selective inhibitor (BLZ945) modulates the induction of human and murine suppressive myeloid cells and efficiently limit tumor progression. While checkpoint inhibitors are insufficient in controlling tumor growth, combining BLZ945 with PD-1/PD-L1 blocking antibodies results in superior tumor control.
  
  
  
  Our results demonstrate the essential role of CSF-1R signaling during the induction of suppressive myeloid cells and emphasize its clinical potential as an immunotherapy for human cancers. Clin Cancer Res; 22(15); 3849-59. ©2016 AACR.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden. Rolf.Kiessling@ki.se Yumeng.Mao@ki.se.
authors.forename: Yumeng
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden.
authors.forename: Nina
authors.initials: N
authors.lastname: Eissler
authors.affiliation: Department of Medicine, Karolinska Institutet, Hematology Centre, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Katarina Le
authors.initials: KL
authors.lastname: Blanc
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden.
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden. Rolf.Kiessling@ki.se Yumeng.Mao@ki.se.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D052160:Benzothiazoles / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D038042:Myelopoiesis; D009447:Neuroblastoma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D010848:Picolinic Acids / Q000494:pharmacology; D011379:Prognosis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C568289:4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D052160:Benzothiazoles; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D010848:Picolinic Acids; D016186:Receptor, Macrophage Colony-Stimulating Factor