Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients

Jennifer S. Ko, Arnold H. Zea, Brian I. Rini, Joanna L. Ireland, Paul Elson, Peter Cohen, Ali Golshayan, Patricia A. Rayman, Laura Wood, Jorge Garcia, Robert Dreicer, Ronald Bukowski, James H. Finke

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597 Scopus citations

Abstract

Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor cells (MDSC) represent one mechanism by which tumors induce T-cell suppression. Several factors pivotal to the accumulation of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression in RCC patients has been investigated. Experimental Design: Patient peripheral blood levels of MDSC and regulatory T-cell (Treg) and T-cell production of IFN-γ were evaluated before and after sunitinib treatment. Correlations between MDSC and Treg normalization as well as T-cell production of IFN-γ were examined. The in vitro effect of sunitinib on patient MDSC was evaluated. Results: Metastatic RCC patients had elevated levels of CD33 + HLA-DR - and CD15 +CD14 - MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression, an effect that could be reproduced by the depletion of MDSC in vitro. MDSC reduction in response to sunitinib correlated with a reversal of CD3 +CD4 +CD25 hiFoxp3 + Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production of IFN-γ. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at ≥1.0 μg/mL. Sunitinib did not induce MDSC maturation in vitro. Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.

Original languageEnglish (US)
Pages (from-to)2148-2157
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number6
DOIs
StatePublished - Mar 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ko, J. S., Zea, A. H., Rini, B. I., Ireland, J. L., Elson, P., Cohen, P., Golshayan, A., Rayman, P. A., Wood, L., Garcia, J., Dreicer, R., Bukowski, R., & Finke, J. H. (2009). Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clinical Cancer Research, 15(6), 2148-2157. https://doi.org/10.1158/1078-0432.CCR-08-1332