title: Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo.
abstract: Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo. Using the Eμ-TCL1 mouse model, we observed severe skewing of myeloid cell populations with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes also accumulated in the spleen in a CCR2-dependent manner, and were severely skewed toward Ly6C(low) patrolling or nonclassical phenotype. In addition, the percentage of MHC-II(hi) dendritic cells and macrophages significantly dropped in the spleen. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression and secretion of multiple inflammatory and immunosuppressive cytokines like interleukin-10, tumor necrosis factor-α and CXCL9. In vivo myeloid cell depletion using liposomal Clodronate resulted in a significant control of CLL development accompanied by a pronounced repair of innate immune cell phenotypes and a partial resolution of systemic inflammation. In addition, CLL-associated skewing of T cells toward antigen-experienced phenotypes was repaired. The presented data suggest that targeting nonmalignant myeloid cells might serve as a novel immunotherapeutical strategy for CLL.
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: B S
authors.initials: BS
authors.lastname: Hanna
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Centre for Haemato-Oncology, Barts Cancer Institute, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: McClanahan
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Yazdanparast
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department for Hematology, Paracelsus Private Medical University Hospital, Salzburg, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Zaborsky
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Kalter
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P M
authors.initials: PM
authors.lastname: Rößner
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Benner
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Dürr
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department for Hematology, Paracelsus Private Medical University Hospital, Salzburg, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Egle
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, UK.
authors.forename: J G
authors.initials: JG
authors.lastname: Gribben
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Seiffert
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D054370:Chemokine CXCL9 / Q000235:genetics / Q000276:immunology; D004002:Clodronic Acid / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010529:Peritoneal Cavity / Q000473:pathology; D010641:Phenotype; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000950:Antigens, Ly; D060890:B7-H1 Antigen; C515335:Ccr2 protein, mouse; C498919:Cd274 protein, mouse; D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; C556062:IL10 protein, mouse; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D016753:Interleukin-10