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B cells and macrophages pursue a common path toward the development and progression of chronic lymphocytic leukemia

Leukemia volume 30, pages 2293–2301 (2016)Cite this article

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Abstract

The development and progression of chronic B-cell tumors depend on a complex microenvironmental network of cells that include monocyte-derived macrophages. In chronic lymphocytic leukemia (CLL) the survival of malignant cells is supported in vitro by nurse-like cells, which differentiate from CD14+ monocytes and have been identified as tumor-associated macrophages (TAMs). The role of the monocyte/macrophage lineage in CLL has been extensively studied in vitro, but only recently has been investigated in in vivo models. We here discuss how the cellular and molecular interactions that physiologically occur between B cells and macrophages can be subverted in chronic B lymphoid malignancies. Clinical approaches for the therapeutic targeting of TAMs are under evaluation. Promising strategies, along with a direct impact on the malignant cells, affect crucial pathways involved in the interaction of leukemic cells with TAMs. As an example, ibrutinib reduces CLL cell chemoattraction by inhibiting macrophage secretion of CXCL13. Lenalidomide and trabectedin prevent TAM recruitment mainly through CCL2 blockade. Most advanced strategies aim at depleting macrophages by targeting the CSF1/CSF1R pathway, which is fundamental for TAM survival. Of note, CSF1 transcripts are significantly more abundant in progressive CLL patients when compared with stable CLL and the frequency of CSF1R+ TAMs correlates with poor survival in hematological malignancies. The successful combination of CSF1R inhibition with currently available agents targeting malignant cells might represent the next therapeutic frontier in CLL. Conceivably these approaches may become applicable to numerous chronic B lymphoid malignancies.

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Acknowledgements

This project was supported by CLL Global Research Foundation and by Associazione Italiana per la Ricerca sul Cancro (AIRC; Program Molecular Clinical Oncology-5 per mille number 9965), Milan, Italy. Figures were obtained using Servier Medical Art: www.servier.com.

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Author notes

  1. G Galletti, F Caligaris-Cappio & M T S Bertilaccio

    Present address: 4Current address: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1901 East Road, Houston, TX 77054, USA.,

  2. F Caligaris-Cappio: Professor F Caligaris-Cappio is presently scientific director of AIRC (Associazione Italiana per la Ricerca sul Cancro), Via S. Vito 7, 20123 Milan, Italy.

Authors and Affiliations

  1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Galletti & M T S Bertilaccio

  2. Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    G Galletti, F Caligaris-Cappio & M T S Bertilaccio

  3. Vita-Salute San Raffaele University, Milan, Italy

    G Galletti, F Caligaris-Cappio & M T S Bertilaccio

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  1. G Galletti
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Correspondence to F Caligaris-Cappio or M T S Bertilaccio.

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MTSB has received research funding from Roche and Celgene. The remaining authors declare no conflict of interest.

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Galletti, G., Caligaris-Cappio, F. & Bertilaccio, M. B cells and macrophages pursue a common path toward the development and progression of chronic lymphocytic leukemia. Leukemia 30, 2293–2301 (2016). https://doi.org/10.1038/leu.2016.261

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