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The kinase inhibitors sunitinib and sorafenib differentially affect NK cell antitumor reactivity in vitro

Matthias Krusch1, Julia Salih, Manuela Schlicke

  • 1Department of Hematology and Oncology, Eberhard Karls-University, Tuebingen, Germany.

Journal of Immunology (Baltimore, Md. : 1950)
|December 17, 2009
PubMed

Insights

Sorafenib, but not Sunitinib, inhibits natural killer (NK) cell antitumor immunity at therapeutic doses. This finding is crucial for combining protein kinase inhibitors (PKI) with immunotherapy for renal cell cancer (RCC).

Area of Science:

  • Immunology
  • Pharmacology
  • Oncology

Background:

  • Advanced renal cell cancer (RCC) treatment often involves protein kinase inhibitors (PKI) like Sunitinib and Sorafenib.
  • Long-term remissions in RCC are linked to robust antitumor immune responses, often enhanced by IL-2 therapy.
  • PKIs may impact not only tumor cells but also the immune effector cells crucial for antitumor immunity.

Purpose of the Study:

  • To investigate the effects of Sunitinib and Sorafenib on antitumor immune responses in RCC patients.
  • To determine how these PKIs influence the function and signaling of immune effector cells, particularly NK cells.
  • To provide insights into the optimal selection and dosing of PKIs when combined with immunotherapeutic strategies.

Main Methods:

  • Assessed the impact of Sunitinib and Sorafenib on peripheral blood mononuclear cell (PBMC) cytotoxicity and cytokine production.
  • Analyzed granule mobilization and NK cell reactivity in response to tumor targets and IL-2 stimulation.
  • Investigated the phosphorylation status of key signaling pathways (PI3K and ERK) in NK cells upon PKI treatment.

Main Results:

  • Sorafenib significantly inhibited PBMC cytotoxicity and cytokine production at pharmacologically relevant concentrations, unlike Sunitinib.
  • Impaired NK cell reactivity, including reduced cytotoxicity and IFN-gamma secretion, was observed with Sorafenib, linked to inhibited PI3K and ERK phosphorylation.
  • Sunitinib demonstrated no significant impact on NK cell effector functions or signaling, even at concentrations achieved during recommended dosing.

Conclusions:

  • Sorafenib can suppress crucial NK cell-mediated antitumor immunity at therapeutic concentrations, potentially limiting its efficacy in combination with immunotherapy.
  • Sunitinib appears to preserve NK cell function, suggesting it may be a more compatible choice for combination therapies involving immune stimulation.
  • Careful consideration of PKI choice and dosage is essential for optimizing cancer treatment strategies that integrate targeted therapy with immunotherapy.

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