Sorafenib inhibits activation of human peripheral blood T cells by targeting LCK phosphorylation

Abstract

Sorafenib, a novel drug for metastatic renal cancer, has broadspectrum activity against multiple tyrosine kinases, including Raf-1, vascular endothelial growth factor receptor and plateletderived growth factor receptor. However, little is known about its effects on the immune system. In this report, we examine the effects of sorafenib on the proliferation and activation of human peripheral blood T cells, as well as its effects on T-cell-mediated immune response in mice. At concentrations similar to those used in patients, sorafenib inhibited the proliferation of primary human T cells in vitro. At more than 10 lM, sorafenib caused an irrecoverable inhibition of proliferation, even after drug withdrawal. In addition, sorafenib induced T-cell apoptosis at concentrations higher than 10 lM. sorafenib also caused G 0 /G 1 phase arrest, inhibition of CD25 and CD69 expression, interleukin-2 production and LCK phosphorylation in the T cells; all of these effects exhibited dose and time dependence. When tested against contact dermatitis in mice, sorafenib significantly reduced the ear swelling induced by picryl chloride. These findings suggest that sorafenib may cause the loss of T-cell immune response by inducing apoptosis and targeting LCK. This could potentially lead to immunosuppression in patients with cancer.

B-Raf Regulation of Integrin α4β1-mediated Resistance to Shear Stress through Changes in Cell Spreading and Cytoskeletal Association in T Cells

“…Sorafenib is a multikinase inhibitor once higher concentrations have been reached, but it is most specific for C-Raf (6 nM IC 50 ) and B-Raf (22 nM IC 50 ) and is still used in the clinic for the treatment of advanced renal cell carcinoma or hepatocellular carcinoma (29). The findings presented in this work should cause a reevaluation of clinical use of sorafenib having potential off-target effects on T cells (72)(73)(74). The effects of sorafenib on ␣4␤1 integrin could impact T cell migration and homing to sites of inflammation or potentially effector functions (75)(76)(77).…”

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1

“…This was associated with an inhibition of Lck-phosphorylation, 23 a Src family kinase involved in T-cell receptor signalling. Sorafenib appears to interact with Lck because the adenosine triphosphate-binding pocket of Lck closely resembles that of PDGFRs.…”

“…These data rule out a role of Lck for sorafenib-induced cell death in CLL cells. However, the inhibitory effects of sorafenib on T-cell activation 23 may also have beneficial effects for the treatment of CLL. Since CLL cells require signals from the T-cell compartment, such as CD40L, targeting autologous T cells in CLL patients may constitute a different mechanism of action.…”

“…This anti-proliferative effect was accompanied by inhibition of the Src-family kinase Lck. 23 Lck shares homology in the adenosine triphosphatebinding domain with Raf, VEGFR and PDGFR and is normally expressed in T cells. However, Lck expression was described previously in 33 patients with CLL.…”

MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib

“…These results are in agreement with several recently published findings. Zhao et al showed that sorafenib inhibits activation and proliferation of lymphocytes in vitro (31). Moreover, using a mouse model with picryl chloride-induced contact dermatitis, sorafenib inhibited the extent of the induced allergic reaction in vivo.…”