Sharma Sherven, Yang Seok-Chul, Hillinger Sven, Zhu Li X, Huang Min, Batra Raj K, Lin Jeff F, Burdick Marie D, Strieter Robert M, Dubinett Steven M
Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Mol Cancer. 2003 Apr 15;2:22. doi: 10.1186/1476-4598-2-22.
SLC/CCL21, normally expressed in high endothelial venules and in T cell zones of spleen and lymph nodes, strongly attracts T cells and dendritic cells (DC). We have previously shown that SLC/CCL21-mediated anti-tumor responses are accompanied by significant induction of IFNgamma and the CXC chemokines, monokine induced by IFNgamma (MIG/CXCL9) and IFNgamma-inducible protein-10 (IP-10/CXCL10).
We assessed the importance of IFNgamma, IP-10/CXCL10 and MIG/CXCL9 in SLC/CCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9 or IFNgamma significantly reduced the anti-tumor efficacy of SLC/CCL21. Assessment of cytokine production at the tumor site showed an interdependence of IFNgamma, MIG/CXCL9 and IP-10/CXCL10; neutralization of any one of these cytokines caused a concomitant decrease in all three cytokines. Similarly, neutralization of any one of these cytokines led to a decrease in the frequency of CXCR3+ve T cells and CD11c+ve DC at the tumor site.
These findings indicate that the full potency of SLC/CCL21-mediated anti-tumor responses require in part the induction of IFNgamma, MIG/CXCL9 and IP-10/CXCL10.
SLC/CCL21通常在高内皮微静脉以及脾脏和淋巴结的T细胞区表达，能强烈吸引T细胞和树突状细胞（DC）。我们之前已经表明，SLC/CCL21介导的抗肿瘤反应伴随着IFNγ以及CXC趋化因子、IFNγ诱导的单核细胞趋化蛋白（MIG/CXCL9）和IFNγ诱导蛋白-10（IP-10/CXCL10）的显著诱导。
我们评估了IFNγ、IP-10/CXCL10和MIG/CXCL9在SLC/CCL21治疗中的重要性。体内去除IP-10/CXCL10、MIG/CXCL9或IFNγ会显著降低SLC/CCL21的抗肿瘤疗效。对肿瘤部位细胞因子产生的评估显示IFNγ、MIG/CXCL9和IP-10/CXCL10之间存在相互依赖性；中和这些细胞因子中的任何一种都会导致这三种细胞因子同时减少。同样，中和这些细胞因子中的任何一种都会导致肿瘤部位CXCR3阳性T细胞和CD11c阳性DC的频率降低。
这些发现表明，SLC/CCL21介导的抗肿瘤反应的全部效力部分需要诱导IFNγ、MIG/CXCL9和IP-10/CXCL10。
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