Targeting dysfunctional myeloid cells delays disease development and improves immune function in a CLL mouse model (TUM6P.1009)

Abstract

Abstract Previous in vitro studies have shown that myeloid cells play a key role in apoptosis-resistance in chronic lymphocytic leukemia (CLL). However, their composition and function have not been thoroughly investigated in vivo. Using the Eµ-TCL1 mouse model of CLL, we observed severe skewing of myeloid cell populations along with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes expressing high levels of inflammatory factors like IL-10, TNFα and CXCL9 accumulated also in the spleen, the main site of disease, and were severely skewed towards Ly6Clow phenotype. Along with that, the percentage of MHC-IIhi dendritic cells (DCs) and macrophages significantly dropped in the spleen, suggesting monocyte differentiation arrest. Myeloid cell depletion using liposomal clodronate resulted in a significant control of CLL development, repair of innate immune cell phenotypes and partial resolution of systemic inflammation. Also, CLL-induced loss of naive T cells was resolved. CLL-associated monocytes and DCs aberrantly express high PD-L1 levels suggesting their contribution in T cell defects. Importantly, PD-L1 blockade very effectively prevented CLL development and was accompanied with a re-activation of immune effector cells. This included restoration of mature macrophages and MHC-IIhi DCs. Our preclinical data suggests that targeting myeloid cell survival and immunosuppression can serve as a novel strategy for CLL immunotherapy.