IL-21 induces tumor rejection by specific CTL and IFN-γ-dependent CXC chemokines in syngeneic mice
IL-21 induces tumor rejection by specific CTL and IFN-γ-dependent CXC chemokines in syngeneic mice
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DOI：
10.4049/jimmunol.172.3.1540
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发表时间：
2004-02-01
影响因子：
4.4
通讯作者：
Ferrini, S
中科院分区：
文献类型：
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作者：
Di Carlo, E;Comes, A;Ferrini, S
IL-21是一种免疫刺激因子，由活化的T细胞产生。为了研究IL-21的体内抗肿瘤活性，对TS/A小鼠乳腺腺癌细胞进行基因修饰，使其分泌IL-21 （TS/A-IL-21）。这些细胞发育成小肿瘤，随后被90%注射sc的同基因小鼠排斥。注射后第5天，TS/ a - il -21肿瘤出现大量浸润的粒细胞、NK细胞和少量CD8(+) T细胞，同时表达tnf - α、ifn - γ和内皮粘附分子ICAM-1和VCAM-1。第7天，CD8（+）和CD4(+) T细胞与ifn - γ、CXC趋化因子ifn - γ诱导蛋白10、ifn - γ诱导的单因子和ifn -诱导T细胞α -趋化剂一起增加。TS/ a - il -21肿瘤显示血管网络中断，萌芽流产和内皮细胞损伤的迹象。特异性抗体的体内消耗实验表明，TS/A-IL-21细胞的排斥反应需要CD8(+) T淋巴细胞和粒细胞。当注射到ifn - γ缺乏的小鼠时，TS/ a- il -21细胞形成的肿瘤仅在29%的动物中消退，这表明ifn - γ在il -21介导的抗肿瘤反应中起作用，但也存在ifn - γ不依赖的作用。再攻毒实验表明，大多数拒绝TS/A-IL-21细胞的免疫能力小鼠对TS/A-pc（75%）和抗基因相关的C26结肠癌细胞（61%）产生保护性免疫。在小鼠排斥TS/A- il -21细胞中，检测到一种由TS/A和C26细胞共表达的内源性小鼠逆转录病毒对gp70-env蛋白的特异性CTL反应。这些数据表明IL-21是诱导特异性CTL反应的合适佐剂。
IL-21 is an immune-stimulatory four a helix cytokine produced by activated T cells. To study the in vivo antitumor activities of IL-21, TS/A murine mammary adenocarcinoma cells were genetically modified to secrete IL-21 (TS/A-IL-21). These cells developed small tumors that were subsequently rejected by 90% of s.c. injected syngeneic mice. Five days after injection, TS/A-IL-21 tumors showed numerous infiltrating granulocytes, NK cells, and to a lesser extent CD8(+) T cells, along with the expression of TNF-alpha, IFN-gamma, and endothelial adhesion molecules ICAM-1 and VCAM-1. At day 7, CD8(+) and CD4(+) T cells increased together with IFN-gamma, and the CXC chemokines IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-inducible T cell alpha-chemoattractant. The TS/A-IL-21 tumor displayed a disrupted vascular network with abortive sprouting and signs of endothelial cell damage. In vivo depletion experiments by specific Abs showed that rejection of TS/A-IL-21 cells required CD8(+) T lymphocytes and granulocytes. When injected in IFN-gamma-deficient mice, TS/A-IL-21 cells formed tumors that regressed in only 29% of animals, indicating a role for IFN-gamma in IL-21-mediated antitumor response, but also the existence of IFN-gamma-independent effects. Most immunocompetent mice rejecting TS/A-IL-21 cells developed protective immunity against TS/A-pc (75%) and against the anti-genically related C26 colon carcinoma cells (61%), as indicated by rechallenge experiments. A specific CTL response against the gp70-env protein of an endogenous murine retrovirus coexpressed by TS/A and C26 cells was detected in mice rejecting TS/A-IL-21 cells. These data suggest that IL-21 represents a suitable adjuvant in inducing specific CTL responses.