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Leukemia. 2016 Mar;30(3):570-9. doi: 10.1038/leu.2015.305. Epub 2015 Nov 2.

Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo.

Author information

1
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Centre for Haemato-Oncology, Barts Cancer Institute, London, UK.
3
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department for Hematology, Paracelsus Private Medical University Hospital, Salzburg, Austria.
4
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

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.

PMID:
26522085
DOI:
10.1038/leu.2015.305
[Indexed for MEDLINE]

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