Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients
Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients
复制标题
DOI：
10.1158/1078-0432.ccr-08-1332
复制
发表时间：
2009-03-15
影响因子：
11.5
通讯作者：
Finke, James H.
中科院分区：
文献类型：
--
作者：
Ko, Jennifer S.;Zea, Arnold H.;Finke, James H.
目的：肾细胞癌（RCC）患者的免疫功能障碍可能导致肿瘤进展。骨髓源性抑制细胞 (MDSC) 是肿瘤诱导 T 细胞抑制的一种机制。酪氨酸激酶抑制剂舒尼替尼针对 MDSC 积累的几个关键因素。研究了舒尼替尼对 RCC 患者 MDSC 介导的免疫抑制的影响。实验设计：在舒尼替尼治疗前后评估患者外周血中 MDSC 和调节性 T 细胞 (Treg) 的水平以及 T 细胞产生的 IFN-γ。检查了 MDSC 和 Treg 正常化以及 T 细胞产生 IFN-γ 之间的相关性。评价舒尼替尼对患者MDSC的体外作用。结果：转移性RCC患者的CD33(+)HLA-DR-和CD15(+)CD14(-)MDSC水平升高，且这些人群是部分重叠的人群。舒尼替尼治疗导致根据多项标准测量的 MDSC 显着减少。舒尼替尼介导的 MDSC 减少与 1 型 T 细胞抑制的逆转相关，这种效应可以通过体外消除 MDSC 来重现。舒尼替尼引起的 MDSC 减少与 CD3(+)CD4(+)CD25(hi)Foxp3(+) Treg 细胞升高的逆转相关。肿瘤负荷的变化与 MDSC、Treg 或 T 细胞产生 IFN-γ 的变化之间不存在相关性。当使用浓度 >= 1.0 μg/mL 时，体外添加舒尼替尼会降低 MDSC 活力和抑制效果。舒尼替尼在体外不会诱导 MDSC 成熟。结论：基于舒尼替尼的治疗有可能通过逆转 MDSC 介导的肿瘤诱导的免疫抑制来调节抗肿瘤免疫。
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-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 mu g/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.