The Kinase Inhibitors Sunitinib and Sorafenib Differentially Affect NK Cell Antitumor Reactivity In Vitro

Abstract

Sunitinib and Sorafenib are protein kinase inhibitors (PKI) approved for treatment of patients with advanced renal cell cancer (RCC). However, long-term remissions of advanced RCC have only been observed after IL-2 treatment, which underlines the importance of antitumor immune responses in RCC patients. Because PKI, besides affecting tumor cells, also may inhibit signaling in immune effector cells, we determined how Sunitinib and Sorafenib influence antitumor immunity. We found that cytotoxicity and cytokine production of resting and IL-2-activated PBMC are inhibited by pharmacological concentrations of Sorafenib but not Sunitinib. Analysis of granule-mobilization within PBMC revealed that this was due to impaired reactivity of NK cells, which substantially contribute to antitumor immunity by directly killing target cells and shaping adaptive immune responses by secreting cytokines like IFN-γ. Analyses with resting and IL-2-activated NK cells revealed that both PKI concentration dependently inhibit cytotoxicity and IFN-γ production of NK cells in response to tumor targets. This was due to impaired PI3K and ERK phosphorylation which directly controls NK cell reactivity. However, while Sorafenib inhibited NK cell effector functions and signaling at levels achieved upon recommended dosing, pharmacological concentrations of Sunitinib had no effect, and this was observed upon stimulation of NK cell reactivity by tumor target cells and upon IL-2 treatment. In light of the important role of NK cells in antitumor immunity, and because multiple approaches presently aim to combine PKI treatment with immunotherapeutic strategies, our data demonstrate that choice and dosing of the most suitable PKI in cancer treatment requires careful consideration.

Sunitinib does not impair natural killer cell function in patients with renal cell carcinoma

“…The present study has confirmed in vivo what was previously demonstrated by Krusch et al (16) in vitro; specifically, there is no negative influence to NK cells CD107a expression and no decline in cytokine production, including of IFN-γ, by PBMC when treated with sunitinib. The enhanced activity rate of PBMC and NK cells during and prior to therapy with sunitinib may be associated with the underlying disease mechanics of mRCC.…”

“…Within the last two decades, numerous new strategies have been developed to improve overall survival, quality of life and disease regression in patients with advanced RCC (1,(4)(5)(6)16,19), and TKI therapy has been shown to be an important treatment modality in addressing these objectives (10,12,13). Nevertheless, data are limited on how TKIs may interact with the immune system of an individual patient (16,19).…”

“…Nevertheless, data are limited on how TKIs may interact with the immune system of an individual patient (16,19). The present study analyzed the influence of the TKI sunitinib on the cellular immunity of three patients with mRCC, focusing specifically on NK cell phenotype and functionality as potential targets for novel immunomodulatory treatment options.…”

“…However, the interaction of sunitinib with the natural killer (NK) cells in the patient is of particular interest (16). NK cells are able to mediate antitumor effects and have thus been used for NK cell adoptive therapy in recent clinical trials (17).…”

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

“…Sorafenib reportedly inhibits cytotoxicity and IFNg production of both resting and activated human NK cells (39). In mice, sorafenib reduced the number of NK cells and their activity against tumor cells (40).…”