CD40 signaling instructs chronic lymphocytic leukemia cells to attract monocytes via the CCR2 axis

Abstract

Chronic lymphocytic leukemia (CLL) cells are provided with essential survival and proliferative signals in the lymph node microenvironment. Here, CLL cells engage in various interactions with bystander cells such as T cells and macrophages. Phenotypically distinct types of tumor infiltrating macrophages can either be tumor supportive (M2) or play a role in tumor immune surveillance (M1). Although recent in vitro findings suggest a protective role for macrophages in CLL, the actual balance between these macrophage subsets in CLL lymphoid tissue is still unclear. Furthermore, the mechanism of recruitment of monocytes towards the CLL lymph node is currently unknown. Both questions are addressed in this paper. Immunofluorescence staining of lymph node samples showed macrophage skewing towards an M2 tumor-promoting phenotype. This polarization likely results from CLL-secreted soluble factors, as both patient serum and CLL-conditioned medium recapitulated the skewing effect. Considering that CLL cell cytokine secretion is affected by adjacent T cells, we next studied CLL-mediated monocyte recruitment in the presence or absence of T-cell signals. While unstimulated CLL cells were inactive, T cell-stimulated CLL cells actively recruited monocytes. This correlated with secretion of various chemokines such as C-C-motif-ligand-2,3,4,5,7,24, C-X-C-motif-ligand-5,10, and Interleukin-10. We also identified CD40L as the responsible T-cell factor that mediated recruitment, and showed that recruitment critically depended on the C-C-motif-chemokine-receptor-2 axis. These studies show that the shaping of a tumor supportive microenvironment depends on cytokinome alterations (including C-C-motif-ligand-2) that occur after interactions between CLL, T cells and monocytes. Therefore, targeted inhibition of CD40L or C-C-motif-chemokine-receptor-2 may be relevant therapeutic options.

Duvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical activity in indolent non‐Hodgkin lymphoma in a phase 1 study

“…In an exploratory analysis, a group of 74 serum factors, including chemokines, cytokines, matrix metalloproteinases, and other proteins were evaluated (Supporting Information Table S1). These factors were chosen because of their relevance to the tumor microenvironment in supporting malignant B cells, including cell‐migration, cell‐cell associations, cell‐proliferative, and differentiation functions …”

Serum Chemokine-release Profiles in AML-patients Might Contribute to Predict the Clinical Course of the Disease

“…It is released by stromal cells, various leukocytes, DC, endothelial cells, as well as tumor (e.g. CLL)-cells (van Attekum et al 2017;Salcedo et al 2000;Yoshimura et al 2015). CCL5 is a monocyte-, eosinophil-and lymphocyte-attractant released by fibroblasts, epithelial cells, DC, monocytes/macrophages, platelets, certain tumor cells and T-cells which plays a critical role in chronic inflammatory diseases and progression of malignant disorders (Aldinucci and Colombatti 2014).…”

Targeting the tumor microenvironment in chronic lymphocytic leukemia

“…26 Furthermore, through direct cell-cell contact by coexpressed adhesion molecules such as lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1, and chemokine signaling via the CXC motif chemokine receptor (CXCR)4/CXC ligand (CXCL)12 axis, TME constituents, such as NLC and stromal cells, aid migration and homing of CLL cells into protective niches. 4,18,19,24 Reciprocally, CLL cells release cytokines including interleukin (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-supportive niche. The above highlighted CLL-TME constituents and interactions are summarized in Online Supplementary Figure S1.…”

“… 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 cytotoxic CD8 + T cells and enriched effector cell subpopulations. 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 cytotoxicity.…”

“…Reciprocally, CLL cells release cytokines including interleukin (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-supportive niche. The above highlighted CLL-TME constituents and interactions are summarized in Online Supplementary Figure S1 .…”