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Targeting the tumor microenvironment in CLL
The T-cell compartment in CLL has a complex dual role since it can exert both pro-tumor as well as anti-CLL cyto- toxic activity.10 Recruited CD4+ T helper cells (Th cells) within proliferation centers provide tumor support through CD40/CD40 ligand (CD40L) co-stimulation and cytokine signaling.11,12 In the peripheral blood of patients, T-cell numbers are increased with skewing towards cyto- toxic CD8+ T cells and enriched effector cell subpopula- tions.13 Both CD4+ and CD8+ T-cell subpopulations exhibit functional defects including impaired immune synapse formation with antigen-presenting cells, impaired cytokine production, degranulation, and antitumor cyto- toxicity.14-16 Furthermore, T cells in CLL show increased expression of markers of chronic activation and exhaus- tion, such as programmed cell death protein 1 (PD-1),13,16 contributing to inhibited effector function and impaired immunological synapse formation.15,16 Patients with CLL also have elevated numbers of regulatory T cells (Treg), a subset of immunosuppressive T cells that constitute sig- nificant suppressors of antitumor T-cell responses.17 Thus, Th cells play an important supportive role in CLL, whereas the accumulation of Treg and exhausted cytolytic T cells prevent effective anti-CLL effector functions.
Similarly, myeloid cells in CLL play both tumor-sup- portive and immunosuppressive roles. These cells include nurse-like cells (NLC), which constitute an essential tumor-supporting component of the TME. NLC, generat- ed in vitro, protect CLL cells from spontaneous and drug- induced apoptosis, promote migration, and aid recruit- ment of tumor-supportive T cells.18-20 Importantly, NLC reveal a strong resemblance to tumor-associated macrophages infiltrating lymph node tissue in CLL.21 In contrast, myeloid cells with immunosuppressive proper- ties, termed myeloid-derived suppressor cells (MDSC), accumulate in the peripheral blood of CLL patients.22 In vitro, CLL-induced MDSC suppress T-cell effector function and promote Treg differentiation.23 Thus, MDSC represent a significant immunosuppressive component within the CLL-TME.
Co-culturing CLL cells with bone marrow-derived stro- mal cells or endothelial cells abrogates the spontaneous apoptosis of CLL cells in vitro, highlighting the supportive role of stromal cells in the CLL-TME.24 Stromal cells medi- ate lymphocyte trafficking and homing, and promote CLL survival and proliferation by inducing expression of pro- angiogenetic and anti-apoptotic proteins.19,24 Thus, the CLL-TME constitutes a complex cellular and molecular network that contributes to tumor survival and immune suppression.
The B-cell receptor pathway is a central mechanism by which CLL cells maintain their crucial interaction with the TME. It consists of an antigen-binding transmembrane immunoglobulin connected to downstream regulators including spleen tyrosine kinase (SYK), Bruton tyrosine kinase (BTK), and phosphoinositide-3-kinase δ (PI3Kδ) (Figure 1A). B-cell receptor signaling, recently reviewed elsewhere,25 promotes proliferation, survival, and migra- tion of the malignant clone. Stimulation of B-cell activat- ing factor receptor (BAFF-R) by its ligand B-cell activating factor (BAFF) provided by, for example, NLC in the TME, also promotes important pro-survival and growth sig- nals.26 Furthermore, through direct cell-cell contact by co- expressed adhesion molecules such as lymphocyte func- tion-associated antigen-1 (LFA-1) and intercellular adhe- sion molecule-1, and chemokine signaling via the CXC
motif chemokine receptor (CXCR)4/CXC ligand (CXCL)12 axis, TME constituents, such as NLC and stro- mal cells, aid migration and homing of CLL cells into pro- tectiveniches.4,18,19,24
Reciprocally, CLL cells release cytokines including inter- leukin (IL)-6 and IL-10,27,28 chemokines such as CCL2,12 and extracellular vesicles,4,29 through which they recruit and alter microenvironmental cells, thus inducing a tumor-sup- portive niche. The above highlighted CLL-TME con- stituents and interactions are summarized in Online Supplementary Figure S1.
The immune-subversive milieu preventing the host immune system from eliminating CLL cells also entails a state of clinical immune dysfunction, manifested as an increased risk of infections and autoimmune conditions in patients with CLL.30 Thus, the CLL-TME is not merely a “silent” support system for malignant cells, but contributes significantly to clinical presentation and disease aggres- siveness.
The majority of therapeutic strategies employed hither- to have been designed to target the survival axes of CLL cells, as exemplified by the development of inhibitor drugs targeting the B-cell receptor pathway. However, as our knowledge on the mechanisms of action is expanding, there is emerging evidence that targeted agents modulate immune TME cells and interactions, which likely pro- foundly influences clinical responses. These effects occur both indirectly, through elimination of CLL cells and/or disruption of critical CLL-TME interaction pathways, and directly, through inhibition of targets within the specific TME cells (Figure 1B). Furthermore, some novel treatment modalities rely directly on the engagement and activation of microenvironmental cells for their anti-CLL activity (Figure 1B).
In order to improve tailored treatment options for patients with CLL, and ultimately improve the clinical course of the disease, a better understanding of how cur- rent novel therapies affect the CLL-TME is warranted. Here we review the current knowledge on how novel tar- geted therapies modulate CLL-TME cells and their interac- tions. We discuss implications for future treatment strate- gies and the development of combination therapy, and highlight potential novel therapeutic targets that warrant future exploration.
BTK inhibitors
The introduction of small molecule inhibitors of BTK, a TEC family kinase that plays a crucial role downstream of B-cell receptor signaling, has shifted the paradigm for CLL treatment during the past decade. Ibrutinib (PCI-32765) was the first oral covalent BTK inhibitor to be approved for CLL by the Food and Drug Administration. Second- generation BTK inhibitors, acalabrutinib and zanubruti- nib, are currently being introduced into clinical use.31,32 BTK inhibition by ibrutinib inhibits activation-induced proliferation and induces apoptosis of CLL cells.33 However, a growing number of studies describe effects of ibrutinib on several components of the TME.
Changes in total T-cell numbers induced by ibrutinib are controversial, as studies have documented both increased and decreased total T-cell numbers in patients treated with ibrutinib.34-36 This discrepancy may be due to differences in treatment duration and disease status at the time of fol-
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