Targeting the tumor microenvironment in chronic lymphocytic leukemia

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 niches of lymph nodes, bone marrow, and secondary lymphoid organs, a variety of phenotypically and functionally altered cell types, including T cells, natural killer cells, monocytes/macrophages, endothelial and mesenchymal stroma cells, provide crucial survival signals, along with CLL-cellinduced 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 components of the multifactorial TME are being discovered. Although the majority of therapeutic strategies employed in CLL hitherto have focused on targeting 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 current 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, translational studies, and novel therapeutic targets in clinical trials.

Figure 1.

Overview of targets within the chronic lymphocytic leukemia cell, and mechanisms of tumor microenvironment modulation by targeted agents. (A) The chronic lymphocytic leukemia (CLL) cell including targets within the B-cell receptor pathway and anti-apoptotic pathway. Downstream of the B-cell receptor, BTK is inhibited by ibrutinib, acalabrutinib, and zanubrutinib, and PI3Kδ is inhibited by idelalisib, duvelisib, and umbralisib. The anti-apoptotic protein BCL-2 is inhibited by venetoclax. (B) Direct versus indirect effects of targeted agents, and activation of tumor microenvironment (TME) anti-CLL activity by novel treatment modalities. Inhibition (both on- and off-target) of targets within the specific TME cells are here referred to as direct effects, exemplified by off-target inhibition of ITK in T cells by ibrutinib, and (on-target) inhibition of PI3Kδ in T cells by idelalisib. Changes occurring due to elimination of CLL cells and/or disruption of critical CLL-TME interaction pathways are here referred to as indirect effects, exemplified by CLL tumor-debulking by ibrutinib, idelalisib, or venetoclax, and disruption of protective signaling between nurse-like cells/tumor-associated macrophages and CLL cells by ibrutinib and idelalisib. Chimeric antigen receptor (CAR) T cells, bispecific antibodies, and immune checkpoint blockade immunotherapy rely directly on the engagement and activation of microenvironmental cells for anti- CLL activity. Binding of CAR T cells to CD19 on CLL cells activates cytolytic anti- CLL T-cell activity, bispecific antibodies redirect T cells into CLL cell proximity and engage T-cell anti-tumor activity, and immune checkpoint blockade abrogates checkpoint inhibitory signals unleashing the anti-CLL activity of tumor-infiltrating T cells. CLL: chronic lymphocytic leukemia; BTK: Bruton tyrosine kinase; SYK: spleen tyrosine kinase; PI3Kδ: phosphoinositide-3-kinase δ, BCR: B-cell receptor; TCR: T-cell receptor; ITK: interleukin-2-inducible T-cell kinase BCL-2: B-cell leukemia/lymphoma-2; TME: tumor microenvironment; NLC: nurse-like cells; TAM: tumor-associated macrophages; CAR T: chimeric antigen receptor T cells; CD: cluster of differentiation; PD-1: programmed cell death protein-1; PD-1L: programmed cell death protein-1 ligand.

Figure 2.

Effects of BTK inhibitors on the chronic lymphocytic leukemia tumor microenvironment. Inhibitory effects are represented by bars, stimulatory effects are represented by arrows. Upward arrows indicate increases, downward arrows indicate decreases. CLL: chronic lymphocytic leukemia; TME: tumor microenvironment; BTK: Bruton tyrosine kinase; BTKi: BTK inhibitor; ITK:interleukin-2-inducible T-cell kinase; PI3Kδ: phosphoinositide-3-kinase δ; TCR: T-cell receptor; CD: cluster of differentiation; CD40L: CD40 ligand; IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; PD-1: programmed cell death protein 1; Th: T helper; Treg: regulatory T cell; ADCP: antibody-dependent cellular phagocytosis; VCAM: vascular cell adhesion molecule; VLA, very late antigen; CXCL: CXC motif chemokine; MDSC: myeloid-derived suppressor cells.

Figure 3.

Effects of BCL-2 inhibitors, immunomodulatory drugs, and cereblon E3 ligase modulation on the tumor microenvironment. Inhibitory effects are represented by bars, stimulatory effects are represented by arrows. Upward arrows indicate increases, downward arrows indicate decreases. CLL: chronic lymphocytic leukemia; TME: tumor microenvironment; BCL-2: B-cell lymphoma 2; BCL-2i: BCL-2 inhibitor; IMiD: immunomodulatory drug; CELMoD: cereblon E3 ligase modulator; TCR: T-cell receptor; HLA-DR: human leukocyte antigen DR-isotype; IFN: interferon; PD-1: programmed cell death protein 1; PD-1L: programmed cell death protein-1 ligand; CCL: chemokine ligand.

Figure 4.

Effects of immune checkpoint blockade, chimeric antigen receptor T cells, and bispecific antibodies. Arrows point out the actions of immune checkpoint blockade, chimeric antigen receptor T cells and bispecific antibodies, leading to engagement and activation of the tumor microenvironment for anti-chronic lymphocytic leukemia activity. Upward arrows indicate increases. CLL: chronic lymphocytic leukemia; PD-1: programmed cell death protein 1; PD-1L: programmed cell death protein-1 ligand; Ab: antibody; CAR-T: chimeric antigen receptor T cells; bsAB: bispecific antibodies; TCR: T-cell receptor; CD: cluster of differentiation.