The tumor microenvironment of B-cell chronic lymphocytic leukemia

The CLL tumor microenvironment contains cells and cytokines that support CLL survival. CD14+ monocytes when co-cultured with chronic lymphocytic leukemia (CLL) B- cells can differentiate in vitro into large, round, adherent cells termed "nurse-like cells" (NLC) that can support the survival of CLL cells via the release of B- cell activating factor of tumor necrosis factor family (BAFF). To identify the factor responsible for this property change in CD14+ monocytes, purified CLL cells were cultured for 24hr and collected the cell-free supernatants to generate conditioned media (CLL-CM). CD14+ monocytes of healthy donors cultured in the CLL-CM assumed NLC morphology and acquired high-level BAFF expression similar to CLL/monocyte co-cultures. In contrast, monocytes cultured in non-conditioned media did not acquire such changes. Similar to NLC, monocytes cultured in CLL-CM were able to support CLL survival in vitro. Furthermore, elevated levels of tumor necrosis factor- alpha (TNF-[alpha]) were detected in CLL-CMs. To investigate whether TNF-[alpha] is the soluble factor in CLL-CM that causes CD14+ monocytes to assume properties of NLC, a decoy receptor for TNF-[alpha], TNF-R-Fc, was added to the cultures and showed a significant reduction in BAFF expression in monocytes compared to the IgG control. A similar reduction in BAFF expression was observed when CLL -serum was treated with TNF-R-Fc. Addition of rhTNF- [alpha] to monocytes was not sufficient to induce BAFF expression in monocytes, suggesting other factor(s) interactions. This finding shows a previously unrecognized symbiosis between CLL cells and their microenvironment and could provide a novel target for therapy of CLL and other indolent B-cell lymphoma