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Chronic lymphocytic leukemia

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

Leukemia volume 30, pages 570–579 (2016)Cite this article

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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 Ly6Clow patrolling or nonclassical phenotype. In addition, the percentage of MHC-IIhi 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.

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Acknowledgements

We thank Shaun Miller at Barts Cancer Institute, Nirojah Vijitha at University Clinic of Essen and the microarray unit of the DKFZ Genomics and Proteomics Core Facility for providing valuable technical assistance. We also thank Dr Markus Feuerer and Dr Jan Hettinger for the fruitful discussions. This study was supported by the Helmholtz Virtual Institute ‘Understanding and overcoming resistance to apoptosis and therapy in leukemia’, by the German Cancer Aid, Grant no. 112069, and by the German José Carreras Foundation, Grant no. R12/27 and R14/23. NZ was supported by the Austrian FWF Firnberg-Grant T 516.

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Authors and Affiliations

  1. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    B S Hanna, F McClanahan, H Yazdanparast, V Kalter, P M Rößner, C Dürr, P Lichter & M Seiffert

  2. Centre for Haemato-Oncology, Barts Cancer Institute, London, UK

    F McClanahan & J G Gribben

  3. 3rd Medical Department for Hematology, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Private Medical University Hospital, Salzburg, Austria

    N Zaborsky & A Egle

  4. Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    A Benner

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Hanna, B., McClanahan, F., Yazdanparast, H. et al. Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo. Leukemia 30, 570–579 (2016). https://doi.org/10.1038/leu.2015.305

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