TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy.
TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy.
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DOI：
10.1158/0008-5472.can-13-1314
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发表时间：
2013-12-15
期刊：
影响因子：
11.2
通讯作者：
Kortylewski M
中科院分区：
文献类型：
--
作者：
Gao C;Kozlowska A;Nechaev S;Li H;Zhang Q;Hossain DM;Kowolik CM;Chu P;Swiderski P;Diamond DJ;Pal SK;Raubitschek A;Kortylewski M
癌症放射治疗可能具有免疫原性，但尚不清楚为什么其免疫原性作用很少足以预防肿瘤复发。在这里，我们报告了一种新的Toll受体-9（TLR 9）依赖的机制，启动肿瘤局部放疗后再生长。在局部高剂量肿瘤照射后，全身抑制TLR 9而非TLR 4可延迟B16黑色素瘤、MB 49膀胱癌和CT 26结肠癌小鼠模型中的肿瘤复发。肿瘤消退微环境中的可溶性因子触发了放射治疗后4天内出现的新鲜招募的骨髓细胞中的TLR 9信号传导。TLR 9的致瘤作用依赖于MyD 88/NF-κ B介导的IL-6表达上调，这反过来又导致髓样细胞中Jak/STAT 3信号传导的下游激活。通过比较野生型、TLR 9或STAT 3缺陷型骨髓细胞中的基因表达，我们鉴定了一组独特的TLR 9/STAT 3调控基因，这些基因参与肿瘤促进炎症和血管再生。通过两种骨髓特异性遗传策略阻断STAT 3功能纠正了放疗后TLR 9介导的癌症复发我们的研究结果表明，将局部肿瘤照射与骨髓细胞特异性抑制TLR 9/STAT 3信号传导相结合，可能有助于消除放射抗性癌症。
Cancer radiotherapy may be immunogenic, but it is unclear why its immunogenic effects are rarely sufficient to prevent tumor recurrence. Here we report a novel Toll receptor-9 (TLR9)-dependent mechanism that initiates tumor regrowth after local radiotherapy. Systemic inhibition of TLR9, but not TLR4, delayed tumor recurrence in mouse models of B16 melanoma, MB49 bladder cancer and CT26 colon cancer after localized high-dose tumor irradiation. Soluble factors in the microenvironment of regressing tumors triggered TLR9 signaling in freshly recruited myeloid cells appearing within four days of radiotherapy. The tumorigenic effects of TLR9 depended on MyD88/NF-κB-mediated upregulation of IL-6 expression, which in turn resulted in downstream activation of Jak/STAT3 signaling in myeloid cells. By comparing global gene expression in wild-type, TLR9- or STAT3-deficient myeloid cells derived from irradiated tumors, we identified a unique set of TLR9/STAT3-regulated genes involved in tumor-promoting inflammation and re-vascularization. Blocking STAT3 function by two myeloid-specific genetic strategies corrected TLR9-mediated cancer recurrence after radiation therapy. Our results suggest that combining localized tumor irradiation with myeloid cell-specific inhibition of TLR9/STAT3 signaling may help eliminate radiation-resistant cancers.