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


METHODS
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.


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-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.


CONCLUSIONS
Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.
Ko
Jennifer S
JS
Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
Zea
Arnold H
AH
Rini
Brian I
BI
Ireland
Joanna L
JL
Elson
Paul
P
Cohen
Peter
P
Golshayan
Ali
A
Rayman
Patricia A
PA
Wood
Laura
L
Garcia
Jorge
J
Dreicer
Robert
R
Bukowski
Ronald
R
Finke
James H
JH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D000077210:Sunitinib; D013491:Suppressor Factors, Immunologic / Q000187:drug effects* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D013491:Suppressor Factors, Immunologic; D007371:Interferon-gamma; D000077210:Sunitinib