In chronic lymphocytic leukemia, activation of the thrombopoietin receptor promotes T-cell inhibitory properties, contributing to immunosuppression

In chronic lymphocytic leukemia (CLL), the immune system is skewed towards a suppressive milieu. Levels of thrombopoietin (TPO), promoting cellular immune regulatory activity in immune thrombocytopenic purpura, were shown to be elevated in CLL patients. This study explored TPO as a potential immunomodulator, supporting CLL progression. We evaluated CLL cell-induced expression of TPO receptor (TPO-R) on T-cells and effects of its activation on T-cell responses. CLL cell involvement in TPO generation was also assessed. Baseline TPO-R expression on CD4 + T-cells was found to be higher in CLL patients than in healthy controls (HC). Exposure of HC-T-cells to B-cells, especially to CLL-B-cells stimulated with B-cell activating molecules, resulted in enhanced TPO-R expression on T-cells. CLL-T-cell stimulation with TPO reduced their proliferation and expanded the regulatory T-cell (Treg) population. At baseline, phosphorylation of STAT5, known to impact the Treg phenotype, was elevated in CLL-T-cells relative to those of HC. Exposure to TPO further enhanced STAT5 phosphorylation in CLL-T-cells, possibly driving the observed Treg expansion. The CLL immune milieu is involved in promotion of inhibitory features in T-cells through increased TPO-R levels and TPO-induced intracellular signaling. TPO and its signaling pathway could potentially support immunosuppression in CLL, and may emerge as novel therapeutic targets.