Targeting Dysfunctional Myeloid Cells Delays Disease Development and Improves Immune Function in a Mouse Model of Chronic Lymphocytic Leukemia

Bola Hanna 1 Fabienne McClanahan 1,2 Alexander Egle 3 John Gribben 2 Peter Lichter 1 Martina Seiffert 1
1Molecular Genetics, German Cancer Research Center (dkfz), Germany
2Centre for Haemato-Oncology, Barts Cancer Institute, UK
3Laboratory for Immunological and Molecular Cancer Research (LIMCR), Paracelsus Medical University, Austria

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy that is stringently associated with a tumor-supportive microenvironment and defective anti-tumor immunity. T cells from CLL patients show features of exhaustion, including expression of PD-1, and are highly impaired in immune synapse formation, which is mediated by aberrant expression of several inhibitory receptors like PD-L1 on CLL cells. Our previous work showed that immune checkpoint blockade using anti-PD-L1 effectively prevents disease and restores T-cell activity in a CLL mouse model (McClanahan et al., 2015).

To investigate the role of myeloid cells in the CLL microenvironment, we analyzed their composition and function in the Eµ-TCL1 mouse model of CLL, and observed a severe skewing of monocytes and macrophages along with CLL development. This included an accumulation of M2-like macrophages and Ly6Clow patrolling monocytes and a drop of MHC-IIhigh dendritic cells (DCs). Associated with that, several inflammatory serum factors like IL-10, TNFα and CXCL9 were upregulated in leukemic mice. Myeloid cell depletion using liposomal clodronate resulted in significant control of CLL development, repair of innate immune cell phenotypes and partial resolution of systemic inflammation. Also, CLL-induced T-cell defects were resolved. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression which was confirmed on DCs, suggesting their contribution to defective T-cell responses and treatment success of PD-L1 blockade. Therefore, targeting myeloid cell survival and immunosuppressive activity can serve as a novel strategy for CLL immunotherapy.

McClanahan, F., Hanna, B., Miller, S., Clear, A.J., Lichter, P., Gribben, J.G., and Seiffert, M. (2015). PD-L1 Checkpoint Blockade Prevents Immune Dysfunction and Leukemia Development in a Mouse Model of Chronic Lymphocytic Leukemia. Blood Mar 23. [Epub ahead of print].









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