The microenvironment in mature B-cell malignancies: a target for new treatment strategies

Abstract

Despite major therapeutic advances, most mature B-cell malignancies remain incurable. Compelling evidence suggests that crosstalk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression by promoting malignant B-cell growth and drug resistance. Therefore, disrupting the crosstalk between malignant B cells and their milieu is an attractive novel strategy for treating selected mature B-cell malignancies. Here we summarize the current knowledge about the cellular and molecular interactions between neoplastic B lymphocytes and accessory cells that shape a supportive microenvironment, and the potential therapeutic targets that are emerging, together with the new problems they raise. We discuss clinically relevant aspects and provide an outlook into future biologically oriented therapeutic strategies. We anticipate a paradigm shift in the treatment of selected B-cell malignancies, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role. Such approaches hopefully will help eliminating residual disease, thereby improving our current therapeutic efforts.

Figure 1

Cellular interactions. (A) Marrow and (B) lymphatic tissue microenvironments in mature B-cell tumors. (A) MSCs (arrow), also called reticular cells, are scattered throughout the marrow cavity and constitutively secrete high levels of the chemokine CXCL12 (SDF-1). MSCs colocalize with the vasculature, forming so-called “vascular niches.” CXCL12 secretion by MSC induces CXCL12 gradients that can attract circulating neoplastic B cells via CXCR4 receptors expressed on CLLs, MM, and other malignant B cells. Circulating lymphoma cells may become attracted by CXCL12 gradients to home to the marrow where contact with MSCs provides them with growth and survival signals. Mesenchymal-derived osteoblasts are specialized fibroblasts critical for bone formation and able to secrete CXCL12. Therefore, interaction with osteoblasts is an alternative, additional niche where lymphoma cells can home. These cellular interactions also confer drug resistance to leukemia/lymphoma cells and may therefore account for MRD. (B) In secondary lymphoid tissues, CLL cells and other lymphoma cells can interact with a variety of accessory cells, such as MSCs, monocyte-derived NLCs, which are similar to LAMs, and T cells. The presence of FDCs in lymphoid tissues in CLL is controversial. Formation of proliferation centers is a hallmark of CLL histopathology. Interactions between CLL and accessory cells within proliferation centers are critical for providing growth and survival signals to CLL B cells, inducing their proliferation and resembling interactions between normal, antigen-stimulated B cells and accessory cells (antigen-presenting cells, T cells) during GC reaction. CLL cells outside the proliferation centers are resting and considered the nonproliferative compartment.

Figure 2

Molecular crosstalk between malignant B cells, exemplified for CLL B cells, and the microenvironment. This figure displays the molecules involved in crosstalk between CLL cells and accessory cells in the marrow and/or lymphoid tissue microenvironments. Contact between CLL cells (and various other mature B-cell lymphomas, as detailed in the text) and NLCs/LAMs or MSCs is established and maintained by chemokine receptors and adhesion molecules. NLCs express the chemokines CXCL12 and CXCL13, whereas MSCs predominantly express CXCL12. NLCs and MSCs attract CLL cells via the G protein–coupled chemokine receptors CXCR4 and CXCR5, which are expressed at high levels on CLL cells. Integrins, particularly VLA-4 integrins (CD49d), expressed on the surface of CLL cells cooperate with chemokine receptors in establishing cell-cell adhesion through respective ligands on the stromal cells (VCAM-1 and fibronectin/FN). NLCs also express the TNF family members BAFF and a proliferation-inducing ligand, providing survival signals to CLL cells via corresponding receptors (BCMA, TACI, BAFF-R). CD38 expression allows CLL cells to interact with CD31, the ligand for CD38, expressed by stromal and NLCs. Ligation of CD38 activates ZAP-70 and downstream survival pathways. Self and/or environmental antigens (Ag) are considered a key factor in stimulation and expansion of the CLL clone. The nature and source of Ag and its mode of presentation in CLLs are unknown and currently the focus of intensive research. Stimulation of the BCR complex (BCR and CD79a,b) induces downstream signaling by recruitment and activation of Syk and ZAP-70. BCR stimulation and coculture with NLCs also induce CLL cells to secrete high levels of the chemokines CCL3 and CCL4, which are potent T cell–attracting chemokines. Through this mechanism, CLL cells can actively recruit T cells for cognate T-cell interactions with CLL cells. CD40L⁺ T cells are preferentially found in CLL proliferation centers and can interact with CLL cells via CD40. Cytokines secreted by T cells or CLL cells, such as IL-4, or TNF-α are considered important regulators of CLL cell survival. Hedgehog (Hh) proteins, such as the indian (Ihh) and sonic (Shh) hedgehog proteins, are stromal cell–derived factors that can regulate survival of CLL and other mature B-cell malignancies. ROR1, an oncofetal antigen with CLL-restricted expression, may function as receptor for Wnt5a, expressed by stromal cells. Collectively, this crosstalk between CLL cells and accessory cells results in activation of survival and drug resistance pathways, such as those provided by Bcl-2 and Mcl-1.