title: Splenic Marginal Zone Granulocytes Acquire an Accentuated Neutrophil B-Cell Helper Phenotype in Chronic Lymphocytic Leukemia.
abstract: Recruitment of tumor-associated macrophages and neutrophils (TAM and TAN) to solid tumors contributes to immunosuppression in the tumor microenvironment; however, their contributions to lymphoid neoplasms are less clear. In human chronic lymphocytic leukemia (CLL), tumor B cells lodge in lymph nodes where interactions with the microenvironment occur. Tumor cell homing stimulates proliferation, such that engagement of the B-cell receptor is important for malignant progression. In the Eμ-Tcl1 murine model of CLL, we identified gene expression signatures indicative of a skewed polarization in the phenotype of monocytes and neutrophils. Selective ablation of either of these cell populations in mice delayed leukemia growth. Despite tumor infiltration of these immune cells, a systemic inflammation was not detected. Notably, in progressive CLL, splenic neutrophils were observed to differentiate toward a B-cell helper phenotype, a process promoted by the induction of leukemia-associated IL10 and TGFβ. Our results suggest that targeting aberrant neutrophil differentiation and restoring myeloid cell homeostasis could limit the formation of survival niches for CLL cells. Cancer Res; 76(18); 5253-65. ©2016 AACR.
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Gätjen
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Brand
authors.affiliation: Department of Physics, Philipps-University Marburg, Marburg, Germany. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gerlach
authors.affiliation: Department of Nephrology and Intensive Care Medicine, Experimental and Clinical Research Center, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Kettritz
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Westermann
authors.affiliation: Institute of Pathology; Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
authors.affiliation: Department of Physics, Philipps-University Marburg, Marburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.affiliation: Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany. Translational Oncology, Department of Medicine A, University Hospital Münster, Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. arehm@mdc-berlin.de uhoepken@mdc-berlin.de.
authors.forename: Uta E
authors.initials: UE
authors.lastname: Höpken
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Department of Hematology, Oncology and Tumorimmunology, Charité-University Medicine Berlin, Berlin, Germany. arehm@mdc-berlin.de uhoepken@mdc-berlin.de.
authors.forename: Armin
authors.initials: A
authors.lastname: Rehm
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006098:Granulocytes / Q000276:immunology / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D013154:Spleen / Q000276:immunology / Q000473:pathology; D059467:Transcriptome