NK Cell Anti-Tumor Immune Responses Are Impaired by Sorafenib but Not by Sunitinib

Abstract

Natural killer (NK) cells play an important role in the surveillance of tumors by exerting cellular cytotoxicity and also due to their ability to secrete immunoregulatory cytokines. A variety of intracellular kinases like PI3K, MAPKs or STAT molecules are involved in the regulation of NK cell functions. Therefore, treatment of tumor patients with small molecule inhibitors targeting various protein kinases may also largely affect NK cell anti-tumor reactivity. The multikinase inhibitors Sunitinib (SUTENT®) and Sorafenib (NEXAVAR®) have been approved for the treatment of patients with metastatic Renal Cell Carcinoma (RCC), and are now also being evaluated in various other tumor entities including AML. Both compounds target, among others, PDGF receptors, VEGF receptors, Flt3 and c-kit. Sorafenib additionally inhibits the MAPK pathway members B-RAF and c-RAF. Here we report that Sorafenib but not Sunitinib substantially reduces NK cell cytotoxicity as revealed by analysis of cell surface CD107a expression as a surrogate marker for mobilization of cytolytic granules on NK cells from ten healthy donors. In line, pharmacological levels of Sorafenib but not Sunitinib largely reduced lysis of several solid tumor and leukemia cell lines by primary NK cells, and this inhibitory effect of Sorafenib occurred concentration dependently. Furthermore, Sorafenib but not Sunitinib concentration dependently impaired NK cell IFN-γ production in coculture experiments with different tumor cell lines. Since Sorafenib, in contrast to Sunitinib, also potently inhibits RAF which is involved in MAPK activation we determined the influence of the two compounds on ERK phosphorylation which is important for the activation of NK cell anti-tumor reactivity. While Sunitinib had no effect, Sorafenib, alike the specific MEK inhibitor PD98059, markedly reduced ERK phosphorylation in NK cells. Taken together, out results indicate that NK cell-mediated anti-tumor immune responses are impaired by Sorafenib but not by Sunitinib via inhibition of signaling pathways crucial for NK cell effector functions. Thus, Sunitinib is exquisitely suitable in diseases and for therapeutic approaches which rely on a sufficient anti-tumor immune response like e.g. allogenic stem cell transplantation in AML or immunotherapeutic approaches in RCC patients.