Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma
Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma
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DOI：
10.1200/jco.2005.03.6830
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发表时间：
2006-03-01
影响因子：
45.3
通讯作者：
Kaufman, HL
中科院分区：
文献类型：
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作者：
Cesana, GC;DeRaffele, G;Kaufman, HL
目的 表征接受高剂量推注白细胞介素 2 (IL-2) 治疗的转移性黑色素瘤 (MM) 和肾细胞癌 (RCC) 患者中 CD4(+)CD25(+) 调节性 T 细胞 (Treg) 的数量和功能状态。 患者和方法 MM 或 RCC 患者单次接受高剂量推注 IL-2（每 8 小时 600,000 IU/kg）治疗 中心提供治疗前和治疗后的全血标本。通过Ficoll密度梯度离心分离外周血单核细胞，分成细胞亚群，并通过流式细胞仪分析或用于体外增殖测定。 结果2003年9月至2005年7月期间，57名患者入组该研究，其中48名患者可供分析（45 MM，12 RCC）。 Tregs 被定义为 CD4(+)CD25(hi) T 细胞，与正常供体相比，该亚群在癌症患者中显着升高 (7.75% vs 2.24%)。患者体内的CD4(+)CD25(hi) T细胞库持续表达细胞内FoxP3、CTLA-4，并产生大量IL-10。 Tregs 为 CCR7(+)，其中 50% 代表初始 T 细胞，50% 代表中央记忆 T 细胞。在混合体外增殖测定中，细胞受到功能抑制。给予IL-2后，疾病进展的患者中Tregs的数量和频率增加，但在有客观临床反应的患者中恢复到正常水平。结论 MM和RCC患者中Tregs（定义为CD4（+）CD25（hi）T细胞）的数量增加，高剂量IL-2导致那些对IL-2治疗达到客观临床反应的患者中Tregs显着减少。
Purpose To characterize the number and functional status of CD4(+)CD25(+) regulatory T cells (Tregs) in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) treated with high-dose bolus interleukin-2 (IL-2).Patients and Methods Patients with MM or RCC treated with high-dose bolus IL-2 (600,000 IU/kg every 8 hours) at a single center provided pre- and post-treatment whole blood specimens. Peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation, separated into cellular subsets, and analyzed by flow cytometry or used for in vitro proliferation assays.Results Between September 2003 and July 2005 57 patients were enrolled in the study with 48 patients available for analysis (45 MM, 12 RCC). Tregs were defined as CD4(+)CD25(hi) T cells, and this subset was significantly elevated in the cancer patients compared with normal donors (7.75% v 2.24%). The CD4(+)CD25(hi) T-cell pool in the patients constitutively expressed intracellular FoxP3, CTLA-4, and produced high amounts of IL-10. The Tregs were CCR7(+) with 50% representing naive and 50% central-memory T cells. The cells were functionally suppressive in mixed in vitro proliferation assays. Following IL-2 administration, the number and frequency of Tregs increased in patients with progressive disease but returned to normal levels in patients with objective clinical responses.Conclusion The number of Tregs, defined as CD4(+)CD25(hi) T cells is increased in patients with MM and RCC, High-dose IL-2 resulted in a significant decrease of Tregs in those patients achieving an objective clinical response to IL-2 therapy.