Figure 3.

Leukemia-environment interplay within secondary lymphoid organs. A growth-promoting niche named proliferative center is the result of cross talk between tumor and accessory cells. CLL cells are attracted within LNs through chemokines (i.e., CXCL13 and CCL19/21) secreted by FDC and NLC, that are thought to correspond to leukemia-associated macrophages (LAM). Here, accessory cells provide a proliferative/survival milieu by secreting cytokines like MIF, BAFF and APRIL. CLL cells in turn, stimulate cytokine production by accessory cells, induce stromal cell differentiation through LTαβ/LTβR interaction and recruit NLCs and T cells through CCL3/4 secretion. An exhausted phenotype on T cells is also accomplished by CLL cells, through PD-L1/PD-1 interaction and IL-10 secretion to realize immune escape. Lightning symbols and red letters indicate new therapeutic targets as discussed in the text