Differential inhibition of T cell receptor and STAT5 signalling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia

Abstract

Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signalling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumour immunity in a subset of patients. We studied the impact of dasatinib in CML patients and compared with patients taking other TKI and healthy controls. We found that patients on dasatinib showed inhibition of both TCR and STAT5 signalling pathways, and reduced expression of T effector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of Tregs and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T-cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signalling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signalling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3 mediated T cell exhaustion and preserve anti-tumour immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.