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Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2312-2324
Targeting the tumor microenvironment in chronic lymphocytic leukemia
Rebecka Svanberg,1* Sine Janum,2* Piers E.M. Patten,3 Alan G. Ramsay3 and Carsten U. Niemann1
1Department of Hematology, Rigshospitalet, Copenhagen, Denmark; 2Department of Clinical Haemato-oncology, Bartholomew’s Hospital, Barts Health Trust, London, UK; 3School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
*RS and SJ contributed equally as co-first authors.
ABSTRACT
The tumor microenvironment (TME) plays an essential role in the development, growth, and survival of the malignant B-cell clone in chronic lymphocytic leukemia (CLL). Within the proliferation nich- es of lymph nodes, bone marrow, and secondary lymphoid organs, a vari- ety of phenotypically and functionally altered cell types, including T cells, natural killer cells, monocytes/macrophages, endothelial and mesenchy- mal stroma cells, provide crucial survival signals, along with CLL-cell- induced suppression of antitumor immune responses. The B-cell receptor pathway plays a pivotal role in mediating the interaction between CLL cells and the TME. However, an increasing number of additional compo- nents of the multifactorial TME are being discovered. Although the major- ity of therapeutic strategies employed in CLL hitherto have focused on tar- geting the leukemic cells, emerging evidence implies that modulation of microenvironmental cells and CLL-TME interactions by novel therapeutic agents significantly affect their clinical efficacy. Thus, improving our understanding of CLL-TME interactions and how they are affected by cur- rent therapeutic agents may improve and guide treatment strategies. Identification of novel TME interactions may also pave the road for the development of novel therapeutic strategies targeting the TME. In this review, we summarize current evidence on the effects of therapeutic agents on cells and interactions within the TME. With a growing demand for improved and personalized treatment options in CLL, this review aims at inspiring future exploration of smart drug combination strategies, trans- lational studies, and novel therapeutic targets in clinical trials.
Introduction
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by the clonal expansion of CD5+/CD19+ malignant B cells, and displays a heterogeneous pathology with chromosomal aberrations, recurrent mutations, and microenviron- mental involvement.1 Although characterized by an accumulation of malignant cells in peripheral blood, CLL develops in protective niches and proliferation cen- ters within the bone marrow, lymph nodes, the spleen and, more rarely, the liver.2 These tissues allow close interactions between malignant cells and various host cells constituting the tumor microenvironment (TME). The survival and growth of CLL cells is highly dependent on support from these surrounding microenviron- mental cells that include T cells, monocytes/macrophages, endothelial and mes- enchymal stroma cells, and natural killer (NK) cells.2-5 The complex crosstalk between CLL cells and these essential microenvironmental components is still poorly defined but studies have revealed how these interactions support disease progression and drug resistance.6-9 For an extensive and detailed overview of the CLL-TME constituents and interactions, we refer the reader to previously pub- lished reviews,3-5 as a complete review of the CLL TME is beyond the scope of this review. However, key components and interactions relevant for the contents of this review are briefly highlighted here.
Correspondence:
CARSTEN UTOFT NIEMANN
carsten.utoft.niemann@regionh.dk
Received: August 6, 2020. Accepted: March 31, 2021. Pre-published: April 22, 2021.
https://doi.org/10.3324/haematol.2020.268037 ©2021 Ferrata Storti Foundation
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