Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
PLoS One. 2011;6(11):e27690. doi: 10.1371/journal.pone.0027690. Epub 2011 Nov 16.
Myeloid-derived suppressor cells (MDSC) are induced under diverse pathologic conditions, including neoplasia, and suppress innate and adaptive immunity. While the mechanisms by which MDSC mediate immunosuppression are well-characterized, details on how they develop remain less understood. This is complicated further by the fact that MDSC comprise multiple myeloid cell types, namely monocytes and granulocytes, reflecting diverse stages of differentiation and the proportion of these subpopulations vary among different neoplastic models. Thus, it is thought that the type and quantities of inflammatory mediators generated during neoplasia dictate the composition of the resultant MDSC response. Although much interest has been devoted to monocytic MDSC biology, a fundamental gap remains in our understanding of the derivation of granulocytic MDSC. In settings of heightened granulocytic MDSC responses, we hypothesized that inappropriate production of G-CSF is a key initiator of granulocytic MDSC accumulation. We observed abundant amounts of G-CSF in vivo, which correlated with robust granulocytic MDSC responses in multiple tumor models. Using G-CSF loss- and gain-of-function approaches, we demonstrated for the first time that: 1) abrogating G-CSF production significantly diminished granulocytic MDSC accumulation and tumor growth; 2) ectopically over-expressing G-CSF in G-CSF-negative tumors significantly augmented granulocytic MDSC accumulation and tumor growth; and 3) treatment of naïve healthy mice with recombinant G-CSF protein elicited granulocytic-like MDSC remarkably similar to those induced under tumor-bearing conditions. Collectively, we demonstrated that tumor-derived G-CSF enhances tumor growth through granulocytic MDSC-dependent mechanisms. These findings provide us with novel insights into MDSC subset development and potentially new biomarkers or targets for cancer therapy.
髓系来源的抑制细胞（MDSC）在多种病理条件下诱导产生，包括肿瘤，并抑制先天和适应性免疫。虽然 MDSC 介导免疫抑制的机制已经得到很好的描述，但它们的发展细节仍知之甚少。这进一步复杂化了这样一个事实，即 MDSC 包含多种髓样细胞类型，即单核细胞和粒细胞，反映了分化的不同阶段，并且这些亚群的比例在不同的肿瘤模型中有所不同。因此，人们认为在肿瘤发生过程中产生的炎症介质的类型和数量决定了产生的 MDSC 反应的组成。尽管人们对单核细胞 MDSC 生物学产生了浓厚的兴趣，但我们对粒细胞 MDSC 的起源仍存在根本的认识差距。在粒细胞 MDSC 反应增强的情况下，我们假设 G-CSF 的不适当产生是粒细胞 MDSC 积累的关键启动子。我们在体内观察到大量的 G-CSF，这与多种肿瘤模型中强大的粒细胞 MDSC 反应相关。通过使用 G-CSF 缺失和功能获得方法，我们首次证明：1） 阻断 G-CSF 的产生显著减少了粒细胞 MDSC 的积累和肿瘤生长；2） 在 G-CSF 阴性肿瘤中异位过表达 G-CSF 显著增加了粒细胞 MDSC 的积累和肿瘤生长；3） 用重组 G-CSF 蛋白治疗天真的健康小鼠引起了与肿瘤负荷条件下诱导的非常相似的粒细胞样 MDSC。总的来说，我们证明了肿瘤源性 G-CSF 通过粒细胞 MDSC 依赖性机制增强了肿瘤生长。这些发现为我们提供了 MDSC 亚群发育的新见解，并为癌症治疗提供了潜在的新生物标志物或靶点。
