Skin tumor responsiveness to interleukin-2 treatment and CD8 Foxp3+T cell expansion in an immunocompetent mouse model
Skin tumor responsiveness to interleukin-2 treatment and CD8 Foxp3+T cell expansion in an immunocompetent mouse model
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DOI：
10.1007/s00262-011-1035-1
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发表时间：
2011-09-01
影响因子：
5.8
通讯作者：
Salo, Jonathan C.
中科院分区：
文献类型：
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作者：
Foureau, David M.;McKillop, Iain H.;Salo, Jonathan C.
重组人白介素2(rhIL-2)疗法已被批准用于治疗晚期黑色素瘤患者，但只有10%-15%的患者观察到显着反应。白介素2在体外诱导活化的人CD8 T细胞表达Foxp3，并扩增黑色素瘤患者循环中的CD8 Foxp3+T细胞。采用IL-2反应性(B16-F1、B16-BL6、JB/MS、MCA-205)和无反应性(JB/RH、B16-F10)小鼠皮下肿瘤模型，观察了CD8Foxp3+T细胞在重组人IL-2(50000 U，i.p.)作用下的分布和变化。或SQ，每天两次，连续5天)。在无肿瘤小鼠和皮下荷瘤小鼠模型中，CD8Foxp3+T细胞是一种罕见的自然产生的细胞亚群。CD8Foxp3+T细胞主要位于皮肤引流淋巴结，表达活化的T细胞(CD28(+)、CD44(+))和Treg(CTLA4(+)、PD1(lo/var)、NKG2A(+/var))标记。经重组人IL-2治疗后，携带IL-2无反应性肿瘤动物的循环和肿瘤引流淋巴结中CD8 Foxp3+T细胞的比例显著增加，而携带IL-2反应性肿瘤动物的循环和肿瘤引流淋巴结中CD8 Foxp3+T细胞的百分率无明显变化。这些发现表明，CD8Foxp3+T细胞群对重组人白介素2治疗的反应可以作为免疫活性模型中肿瘤对免疫治疗反应性的早期标志。此外，这些数据可能为预测接受重组人白介素2治疗的黑色素瘤患者的反应提供洞察力。
Recombinant human interleukin-2 (rhIL-2) therapy is approved for treating patients with advanced melanoma yet significant responses are observed in only 10-15% of patients. Interleukin-2 induces Foxp3 expression in activated human CD8 T cells in vitro and expands circulating CD8 Foxp3+ T cells in melanoma patients. Employing IL-2 responsive (B16-F1, B16-BL6, JB/MS, MCA-205) and nonresponsive (JB/RH, B16-F10) subcutaneous tumor mouse models, we evaluated CD8 Foxp3+ T cell distribution and changes in response to rhIL-2 (50,000 U, i.p. or s.q., twice daily for 5 days). In tumor-free mice and subcutaneous tumor-bearing mouse models, CD8 Foxp3+ T cells were a rare but naturally occurring cell subset. Primarily located in skin-draining lymph nodes, CD8 Foxp3+ T cells expressed both activated T cell (CD28(+), CD44(+)) and Treg (CTLA4(+), PD1(lo/var), NKG2A(+/var)) markers. Following treatment with rhIL-2, a dramatic increase in CD8 Foxp3+ T cell prevalence was observed in the circulation and tumor-draining lymph nodes (TD.LNs) of animals bearing IL-2 nonresponsive tumors, while no significant changes were observed in the circulation and TD.LNs of animals bearing IL-2 responsive tumors. These findings suggest expansion of CD8 Foxp3+ T cell population in response to rhIL-2 treatment may serve as an early marker for tumor responsiveness to immunotherapy in an immune competent model. Additionally, these data may provide insight to predict response in patients with melanoma undergoing rhIL-2 treatment.