Role of CXCR3 ligands in IL-7/IL-7R alpha-Fc-mediated antitumor activity in lung cancer.
Role of CXCR3 ligands in IL-7/IL-7R alpha-Fc-mediated antitumor activity in lung cancer.
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DOI：
10.1158/1078-0432.ccr-10-3346
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发表时间：
2011-06-01
期刊：
影响因子：
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通讯作者：
Sharma S
中科院分区：
文献类型：
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作者：
Andersson A;Srivastava MK;Harris-White M;Huang M;Zhu L;Elashoff D;Strieter RM;Dubinett SM;Sharma S
我们评估了嵌合γc稳态细胞因子IL-7/IL-7 R α-Fc在肺癌中恢复宿主APC和T细胞活性的效用。利用小鼠肺癌模型，我们确定了IL-7/IL-7 R α-Fc的抗肿瘤功效。进行APC、T细胞、细胞因子分析、CXCL 9、CXCL 10和IFNγ的中和，以评价IL-7/IL-7 R α-Fc与对照相比的抗肿瘤活性的机制差异。IL-7/IL-7 R α-Fc给药可抑制肺癌的肿瘤生长并延长生存期。伴随肿瘤生长抑制的是APC和T细胞活性的增加。与对照组相比，IL-7/IL-7 R α-Fc处理荷瘤小鼠导致以下增加：i）CXCL 9、CXCL 10、IFNγ、IL-12的水平，但IL-10和TGFβ降低，ii）M1表型的肿瘤巨噬细胞浸润特征，IL-12、iNOS增加，但IL-10和TGF β降低，iii）T和NK细胞的频率，iv）T细胞活化标志物CXCR 3，CD 69和CD 127，低v）效应记忆T细胞和vi）T细胞对亲本肿瘤细胞的细胞溶解活性。IL-7/IL-7 R α-Fc处理消除了肿瘤诱导的脾功能性APC对T应答细胞活性的降低。CXCR 3配体在IL-7/IL-7 R α-Fc介导的抗肿瘤活性中起重要作用。CXCL 9、CXCL 10或IFNγ的中和减少了表达CXCR 3的活化T细胞浸润肿瘤，并消除了IL-7/IL-7 R α-Fc介导的肿瘤生长抑制。我们的研究结果表明，IL-7/IL-7 R α-Fc促进肺癌的传入和传出抗肿瘤反应。
We evaluated the utility of chimeric γc homeostatic cytokine, IL-7/IL-7Rα-Fc, to restore host APC and T cell activities in lung cancer. Utilizing murine lung cancer models we determined the antitumor efficacy of IL-7/IL-7Rα-Fc. APC, T cell, cytokine analyses, neutralization of CXCL9, CXCL10 and IFNγ were performed to evaluate the mechanistic differences in the antitumor activity of IL-7/IL-7Rα-Fc in comparison to controls. IL-7/IL-7Rα-Fc administration inhibited tumor growth and increased survival in lung cancer. Accompanying the tumor growth inhibition were increases in APC and T cell activities. In comparison to controls, IL-7/IL-7Rα-Fc treatment of tumor bearing mice led to increased: i) levels of CXCL9, CXCL10, IFNγ, IL-12 but reduced IL-10 and TGFβ, ii) tumor macrophage infiltrates characteristic of M1 phenotype with increased IL-12, iNOS but reduced IL-10 and arginase, iii) frequencies of T and NK cells, iv) T cell activation markers CXCR3, CD69 and CD127,low v) effector memory T cells and vi) T cell cytolytic activity against parental tumor cells. IL-7/IL-7Rα-Fc treatment abrogated the tumor induced reduction in splenic functional APC activity to T responder cells. The CXCR3 ligands played an important role in IL-7/IL-7Rα-Fc mediated antitumor activity. Neutralization of CXCL9, CXCL10 or IFNγ reduced CXCR3 expressing activated T cells infiltrating the tumor and abrogated IL-7/IL-7Rα-Fc mediated tumor growth inhibition. Our findings demonstrate that IL-7/IL-7Rα-Fc promotes afferent and efferent antitumor responses in lung cancer.