Abstract
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. Patient peripheral blood levels of MDSC and regulatory T-cell (Treg) and T-cell production of IFN-gamma were evaluated before and after sunitinib treatment. Correlations between MDSC and Treg normalization as well as T-cell production of IFN-gamma were examined. The in vitro effect of sunitinib on patient MDSC was evaluated. 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(hi)Foxp3(+) Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production of IFN-gamma. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at >/=1.0 microg/mL. Sunitinib did not induce MDSC maturation in vitro. Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.
Highlights
Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression
Because VEGF has been implicated in the generation of Myeloid-derived suppressor cells (MDSC) [29, 30], we have evaluated the effect of sunitinib, which blocks signaling through multiple receptors, including vascular endothelial growth factor receptors (VEGFR) [11], on MDSC in metastatic RCC patients
We show that treatment with sunitinib in metastatic RCC (mRCC) patients reduces the elevated levels of both MDSC subsets to near normal levels
Summary
Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. 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. Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression. This year f36,000 Americans will be newly diagnosed with kidney cancer, resulting in 12,890 deaths [1]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). VEGF may support tumor growth via negative effects on host antitumor adaptive immunity, as increased VEGF levels have been associated with alterations in myeloid cell differentiation, which impair competent dendritic cell formation and encourage suppressive myeloid cell formation in cancer patients (13 – 18). MDSC detected in the peripheral blood of patients bearing several tumor types (16, 22 – 27) express the common
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