Beyond bystanders: Myeloid cells in chronic lymphocytic leukemia

Tumor-promoting inflammation and escape from immune-mediated tumor destruction have been recognized as hallmarks of cancer, and myeloid cells are key players in these processes. By exploiting the tremendous plasticity of myeloid cells, tumors induce a variety of tumor-supportive and immunosuppressive cell phenotypes like tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). The relevance of these cell types in hematopoietic malignancies has only recently gained a stronger attention. Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that expand in secondary lymphoid organs and the bone marrow, and accumulate in the blood of patients. A large body of evidence suggests that the interactions between CLL cells and non-malignant cells in the tumor microenvironment play a key role in the pathology of this disease. CLL is associated with an inflammatory milieu and defective immune responses. A severe skewing of myeloid and T cells toward leukemia-supportive and immunosuppressive phenotypes have been observed in patient samples and the Eμ-TCL1 mouse model of CLL. Myeloid cells were thereby shown to enhance survival of CLL cells and contribute to apoptosis-resistance, to suppress anti-tumoral immunity, and to be involved in immune deficiency of leukemia patients. In addition, treatment regimens that are currently used for CLL target not only directly the malignant cells, but have also an impact on non-malignant bystander cells, including myeloid cells. This review summarizes current literature on these aspects and gives a perspective on how our current knowledge might be used to design novel immunotherapeutic approaches that can be combined with CLL-targeting drugs to achieve better therapeutic responses in CLL patients.