Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression
Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression
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DOI：
10.1158/0008-5472.can-07-2354
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Ostrand-Rosenberg, Suzanne
中科院分区：
文献类型：
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作者：
Bunt, Stephanie K.;Yang, Linglin;Ostrand-Rosenberg, Suzanne
慢性炎症经常与恶性生长有关，被认为促进和促进了肿瘤的进展，尽管调节这种关系的机制仍然不清楚。我们以前曾报道，白介素2通过促进髓系抑制细胞(MDSC)的积聚来促进肿瘤进展，并假设炎症是通过产生MDSC来抑制肿瘤免疫而导致癌症的。如果炎症诱导的MDSC通过阻断抗肿瘤免疫来促进肿瘤进展，那么炎症的减少应该会降低MDSC的水平并延缓肿瘤的进展，而炎症的增加应该会增加MDSC的水平并加速肿瘤的进展。我们已经用4T1乳腺癌和IL-1受体(IL-1R)缺陷小鼠和IL-1R拮抗剂缺陷小鼠检验了这一假设，前者炎症潜能降低，后者炎症潜能增加。与我们的假设一致，IL-IR缺陷小鼠有延迟的MDSC积聚，并减缓了原发和转移肿瘤的进展。IL-6可部分恢复MDSC的积聚和肿瘤进展，提示IL-6是IL-1β诱导的MDSC扩张的下游介质。相反，IL-1R拮抗剂缺陷小鼠的过度炎症促进了MDSC的积累，并产生了具有增强抑制活性的MDSC。这些结果表明，MDSC的免疫抑制和肿瘤生长受炎症环境的调节，并支持这样的假说，即诱导抑制细胞下调肿瘤免疫是炎症与癌症联系的机制之一。
Chronic inflammation is frequently associated with malignant growth and is thought to promote and enhance tumor progression, although the mechanisms which regulate this relationship remain elusive. We reported previously that interleukin promoted tumor progression by enhancing the accumulation of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation leads to cancer through the production of MDSC which inhibit tumor immunity. If inflammation-induced MDSC promote tumor progression by blocking antitumor immunity, then a reduction in inflammation should reduce MDSC levels and delay tumor progression, whereas an increase in inflammation should increase MDSC levels and hasten tumor progression. We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)-deficient mice which have a reduced potential for inflammation, and IL-1R antagonist-deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-IR-deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1 beta-induced expansion of MDSC. In contrast, excessive inflammation in IL-1R antagonistdeficient mice promotes the accumulation of MDSC and produces MDSC with enhanced suppressive activity. These results show that immune suppression by MDSC and tumor growth are regulated by the inflammatory milieu and support the hypothesis that the induction of suppressor cells which downregulate tumor immunity is one of the mechanisms linking inflammation and cancer.