Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained.
Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained.
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DOI：
10.1158/0008-5472.can-09-3278
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Cohen PA
中科院分区：
文献类型：
--
作者：
Ko JS;Rayman P;Ireland J;Swaidani S;Li G;Bunting KD;Rini B;Finke JH;Cohen PA
抗血管生成药物舒尼替尼是一种受体酪氨酸激酶抑制剂，在转移性肾细胞癌（mRCC）中具有显著但非治愈性的治疗作用。舒尼替尼也是一种免疫调节剂，甚至在无应答RCC患者的血液中也能有效逆转髓源性抑制细胞（MDSC）蓄积和T细胞抑制。我们观察到舒尼替尼类似地阻止了MDSC积累，并恢复了荷瘤小鼠脾脏的正常T细胞功能，与舒尼替尼抑制肿瘤进展的能力无关（RENCA> CT 26> 4 T1）。单核细胞和嗜中性粒细胞的脾脏MDSC都被舒尼替尼高度抑制。相比之下，4 T1肿瘤或人RCC肿瘤微环境中的MDSC对舒尼替尼具有高度耐药性，周围T细胞功能仍然受到抑制。蛋白质组学分析比较肿瘤外周室表明，GM-CSF预测舒尼替尼耐药，和重组GM-CSF赋予舒尼替尼耐药MDSC在体内和体外。用GM-CSF调节MDSC独特地抑制STAT 3并促进STAT 5活化，并且在体外存在GM-CSF的情况下，STAT 5ab（null/null）MDSC对舒尼替尼敏感。我们的结论是，隔室依赖性GM-CSF暴露在耐药肿瘤可能占舒尼替尼的区域化的影响后，主机MDSC调制，并假设辅助策略，以减少这种区域化将增强舒尼替尼作为免疫调节剂和癌症治疗的效力。
The anti-angiogenic drug sunitinib is a receptor tyrosine-kinase inhibitor with significant, yet not curative, therapeutic impacts in metastatic renal cell carcinoma (mRCC). Sunitinib is also an immunomodulator, potently reversing myeloid-derived suppressor cell (MDSC) accumulation and T-cell inhibition in the blood even of non-responder RCC patients. We observed that sunitinib similarly prevented MDSC accumulation and restored normal T-cell function to spleens of tumor-bearing mice, independent of sunitinib's capacity to inhibit tumor progression (RENCA>CT26>4T1). Both monocytic and neutrophilic splenic MDSC were highly repressible by sunitinib. In contrast, MDSC within the microenvironment of 4T1 tumors or human RCC tumors proved highly resistant to sunitinib, and ambient T-cell function remained suppressed. Proteomic analyses comparing tumor to peripheral compartments demonstrated that GM-CSF predicted sunitinib resistance, and recombinant GM-CSF conferred sunitinib resistance to MDSC in vivo and in vitro. MDSC conditioning with GM-CSF uniquely inhibited STAT3 and promoted STAT5 activation, and STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. We conclude that compartment-dependent GM-CSF exposure in resistant tumors may account for sunitinib's regionalized impact upon host MDSC modulation, and hypothesize that ancillary strategies to decrease such regionalization will enhance sunitinib's potency as an immunomodulator and a cancer therapy.