Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients

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...

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Bibliographic Details
Published in:Clinical cancer research 2009-03, Vol.15 (6), p.2148-2157
Main Authors: KO, Jennifer S, ZEA, Arnold H, DREICER, Robert, BUKOWSKI, Ronald, FINKE, James H, RINI, Brian I, IRELAND, Joanna L, ELSON, Paul, COHEN, Peter, GOLSHAYAN, Ali, RAYMAN, Patricia A, WOOD, Laura, GARCIA, Jorge
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Carcinoma, Renal Cell - drug therapy
Carcinoma, Renal Cell - immunology
Female
Humans
Indoles - pharmacology
Indoles - therapeutic use
Interferon-gamma - biosynthesis
Kidney Neoplasms - drug therapy
Kidney Neoplasms - immunology
Kidneys
Male
Medical sciences
Middle Aged
Myeloid Cells - immunology
myeloid-derived suppressor cell (MDSC)
Nephrology. Urinary tract diseases
Pharmacology. Drug treatments
Pyrroles - pharmacology
Pyrroles - therapeutic use
RCC
Suppressor Factors, Immunologic - drug effects
Suppressor Factors, Immunologic - physiology
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - physiology
Tumors of the urinary system
Type 1
tyrosine kinase inhibitor
VEGF
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Summary: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 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-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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-08-1332