The role of CXCR3 in the microenvironment of chronic lymphocytic leukemia

Abstract

Abstract 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 their activity. Our previous work showed that immune checkpoint blockade using anti-PD-L1 effectively prevents disease and restores T-cell activity in the Eμ-TCL1 mouse model of CLL. Development of disease in these mice was shown to be associated with a relative loss of naïve T cells and an enrichment of effector T cells displaying an exhausted phenotype. Our work showed that T cells in the Eμ-TCL1 mice express high levels of the chemokine receptor CXCR3 accompanied with elevated serum levels of the corresponding chemokines CXCL9 and CXCL10, suggesting a role for CXCR3 in T-cell skewing in CLL. Intracellular flow cytometric analysis showed an enrichment of CXCL9+ CD45+ hematopoietic cells in leukemic spleens which were identified as Ly6C+ monocytes. Along this line, depletion of phagocytic cells by Clodronate Liposomes resulted in significantly decreased serum levels of CXCL9, a reversal of T-cell skewing and slowed down development of CLL in mice. To evaluate the role of this receptor in CLL in vivo, adoptive transfer of murine CLL cells in CXCR3 knockout mice is currently ongoing. We further perform an in-depth phenotypical analysis of T-cell subsets in blood samples of CLL patients from different prognostic subgroups to characterize T-cell aberrations along with disease progression. Taken together, our data suggest a pathomechanistic role for CXCL9, CXCL10 and their receptor CXCR3 in CLL. Their potential as novel drug targets needs to be explored in the future.