van Cruijsen Hester, van der Veldt Astrid A M, Vroling Laura, Oosterhoff Dinja, Broxterman Henk J, Scheper Rik J, Giaccone Giuseppe, Haanen John B A G, van den Eertwegh Alfons J M, Boven Epie, Hoekman Klaas, de Gruijl Tanja D
Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
Clin Cancer Res. 2008 Sep 15;14(18):5884-92. doi: 10.1158/1078-0432.CCR-08-0656.
A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT, and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients.
Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex- and age-matched healthy donor data.
Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1(+) MDC frequencies were predictive for tumor regression and improved progression-free survival.
The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression.
髓系谱系发育紊乱，中性粒细胞异常增多，树突状细胞（DC）分化受损，可能导致肿瘤免疫逃逸。我们研究了舒尼替尼（一种针对fms样酪氨酸激酶-3、KIT和血管内皮生长因子受体的酪氨酸激酶抑制剂）对肾细胞癌（RCC）患者髓系分化的影响。
26例晚期RCC患者接受舒尼替尼治疗，采用4周用药/2周停药的方案。在基线以及第一个治疗周期的第4周和第6周对血液中的髓系亚群进行计数和广泛的表型分析。将患者的基线数据与性别和年龄匹配的健康供体数据进行比较。
RCC患者DC亚群的基线频率低于健康供体。舒尼替尼治疗4周后，观察到髓系频率普遍下降。基线时均异常升高的中性粒细胞和单核细胞在停药的2周内仍保持较低水平，而DC比例恢复，导致髓系谱系分布正常化。舒尼替尼治疗后，在肿瘤出现消退的患者中，相对于其他髓系亚群，髓系DC（MDC）亚群频率特异性升高至较高水平。此外，高CD1c/BDCA-1(+) MDC频率可预测肿瘤消退和无进展生存期的改善。
在晚期RCC患者中观察到的舒尼替尼诱导的髓系谱系重新分布与免疫状态改善一致。如在肿瘤消退患者中相对于其他髓系亚群MDC频率大幅增加这一发现所示，免疫恢复可能有助于临床疗效的提高。
