Microenvironment

The tissue microenvironment has an important role in CLL pathogenesis. Microenvironmental stimuli promote cell growth, survival and drug-resistance. Circulating CLL cells in the blood are generally non-proliferating and resting whereas CLL cells in tissues proliferate at a high rate (Zhang & Kipps, 2014). In CLL, the microenvironment interactions primarily occur in specialised compartments of the lymph nodes and bone marrow (Efremov & Laurenti, 2014). Proliferating CLL cells in the tissues interact with accessory cells e.g. T cells, bone marrow stromal cells (BMSCs), nurse-like cells and follicular dendritic cells, via various ligand/receptor interactions which provide proliferation and survival signals (Figure 2, Table 1) (Efremov & Laurenti, 2014; Ten Hacken & Burger, 2014; Zhang & Kipps, 2014).

  • Stromal and nurse-like cells provide pro-survival signals, produce chemokines which, coupled with high expression of relevant chemokine receptors on the CLL cells, mediate homing and retention of CLL cells in tissue compartments.
  • CLL cells from lymphoid tissue and bone marrow have higher expression of transcription factors E2F and MYC compared to CLL cells in the blood.
  • In relevant tissues, especially secondary lymphoid tissue, enhanced BCR signalling (discussed above) and activation of TNF receptors in CLL cells is observed.
  • Nurse-like cells provide pro-survival signals via expression of the TNF BAFF and a ligand that induces proliferation.
  • CLL cell surface integrins (e.g. CD49d) cooperate with chemokine receptors to bind ligands (vascular cell adhesion molecule-1 [VCAM1] and fibronectin) on stromal cells to facilitate cell-cell adhesion.
  • High levels of Wnt5a are expressed by BMSCs which stimulate signalling pathways in CLL that favour survival.
  • CD44 is a receptor for hyaluronic acid which also interacts with a number of proteins expressed by CLL cells (e.g. CD38, CD49d, MMP-9 and ZAP-70) and is important for interaction between CLL cells and the microenvironment.
A diagram showing microenvironmental interactions implicated in the pathogenesis of C L L.

Figure 2. Microenvironmental interactions implicated in the pathogenesis of CLL.
CLL cells interact with CD4+ T cells, stromal cells, nurse-like cells and follicular dendritic cells through various receptors, including CD40, VLA-4, CXCR4, CD38, BAFF-R and the B cell receptor (BCR). These interactions promote CLL survival and induce proliferation.
Reproduced with kind permission from the authors (Efremov & Laurenti, 2014).

Table 1. Cellular components of the CLL microenvironment
Cell type Function in normal tissue Function in CLL microenvironment
BMSC
  • Formation of haematopoietic stem-cell niches/regulation of haematopoiesis
  • Constitutive secretion of CXCL12 and other hematopoietic cytokines
  • Tissue retention of CLL cells
  • CLL cell drug resistance and protection from apoptosis
  • PKC-βII activation in BMSCs induced by CLL cells
NLC N/A
  • Tissue retention of CLL cells
  • CLL cell drug resistance and protection from apoptosis
  • CLL cell attraction by CXCL12 and CXCL13 production
  • BAFF and APRIL expression
  • Activation of BCR and NF-κB pathway genes in CLL cells
  • Disease progression in vivo
  • Interaction with CD38-expressing cells via CD31
CD4+ T cells / Th cells
  • Adaptive immune responses
  • Antigen recognition
  • T-antigen-presenting cell (APC) immune synapse formation
  • APC activation via CD40/CD40L interaction
  • CLL engraftment in vivo
  • Defective immune synapse formation upon contact with CLL cells
  • CD40L+CD4+ T cells induce CLL cells to produce CCL17 and CCL22
  • Increased expression of inhibitory receptors
CD4+CD25high / Treg
  • Inhibition of proliferation and cytokine release by CD4+ T cells
  • Inhibition of antitumor immunity
  • High proportion of CD4+CD25high Treg may contribute to CLL immune evasion
CD8+ T cells / cytotoxic T cells
  • Adaptive immune responses
  • Antigen recognition when presented on MHC class I molecules by target cells (e.g. cancer cells, virally infected cells)
  • Apoptosis induction of target cells
  • Defective immune synapse formation upon contact with CLL cells
  • Exhausted phenotype and impaired cytotoxicity
NK cells
  • Innate immune responses
  • Antigen recognition when presented on MHC class I molecules by target cells (e.g. cancer cells, virally infected cells)
  • Apoptosis induction of target cells
  • Reduced cytotoxicity
  • Low expression of NKp30 activating receptor
APC, antigen-presenting cell; BMSC, bone marrow stromal cell; MHC, major histocompatibility complex; NK, natural killer cell; NLC, nurse-like cell; PKC, protein kinase C; Th cell, T helper cell; Treg cell, regulatory T cell; TNF, tumour necrosis factor (Adapted from Ten Hacken & Burger 2014).