This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.

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 regulatoryT-cell (Treg) and T-cell production of IFN-g were evaluated before and after sunitinib treatment. Correlations between MDSC and Treg normalization as well asT-cell production of IFN-g 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-g. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at z1.0 Ag/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.

Purpose: Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely contributes to tumor evasion. This dysfunction includes a shift from a type-1 to a type-2 T-cell cytokine response and enhanced T-regulatory (Treg) cell expression. Given the antitumor activity of select tyrosine kinase inhibitors such as sunitinib in metastatic RCC (mRCC) patients, it is relevant to assess their effect on the immune system. Experimental Design: Type-1 (IFNg) and type-2 (interleukin-4) responses were assessed in T cells at baseline and day 28 of treatment with sunitinib (50 mg/d) by measuring intracellular cytokines after in vitro stimulation with anti-CD3/anti-CD28 antibodies. Results: After one cycle of treatment, there was a significant increase in the percentage of IFNgproducingTcells (CD3 + , P < 0.001; CD3 + CD4 + , P = 0.001), a reduction in interleukin-4 production (CD3 + cells, P = 0.05), and a diminished type-2 bias (P = 0.005).The increase in type-1response may be partly related to modulation of Treg cells. The increased percentage of Treg cells noted in mRCC patients over healthy donors (P = 0.001) was reduced after treatment, although not reaching statistical significance. There was, however, an inverse correlation between the increase in type-1response after two cycles of treatment and a decrease in the percentage of Treg cells (r = -0.64, P = 0.01). In vitro studies suggest that the effects of sunitinib onTreg cells are indirect. Conclusions: The demonstration that sunitinib improved type-1 T-cell cytokine response in mRCC patients while reducingTreg function provides a basis for the rational combination of sunitinib and immunotherapy in mRCC.