Tumor-Derived G-CSF Facilitates Neoplastic Growth through a Granulocytic Myeloid-Derived Suppressor Cell-Dependent Mechanism

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.

髓系来源抑制细胞（Myeloid-derived suppressor cells，MDSC）可在包括肿瘤发生在内的多种病理状态下被诱导产生，并可抑制固有免疫与适应性免疫。尽管MDSC介导免疫抑制的机制已被充分阐明，但其发育的具体细节仍有待深入解析。而MDSC包含多种髓系细胞亚型，即单核细胞与粒细胞，对应不同分化阶段，且各亚群的比例在不同肿瘤模型中存在差异，这进一步加剧了相关研究的复杂性。因此，学界普遍认为，肿瘤发生过程中产生的炎性介质的类型与丰度，决定了最终MDSC应答的组成特征。尽管学界对单核细胞型MDSC的生物学特性已有大量研究，但我们对粒细胞型MDSC的起源仍存在根本性认知空白。在粒细胞型MDSC应答增强的情况下，我们提出假说：粒细胞集落刺激因子（G-CSF）的异常产生是粒细胞型MDSC聚集的关键启动因素。我们在体内检测到大量G-CSF，其表达水平与多种肿瘤模型中显著增强的粒细胞型MDSC应答呈正相关。通过G-CSF功能缺失与功能过表达实验手段，我们首次证实：1）阻断G-CSF的产生可显著减少粒细胞型MDSC的聚集并抑制肿瘤生长；2）在原本不表达G-CSF的肿瘤中异位过表达G-CSF，可显著促进粒细胞型MDSC的聚集并加速肿瘤生长；3）用重组G-CSF蛋白处理未致敏的健康小鼠，可诱导产生与荷瘤状态下诱导的粒细胞型MDSC表型高度相似的细胞群。综上，我们证实肿瘤来源的G-CSF可通过依赖粒细胞型MDSC的机制促进肿瘤生长。本研究结果为MDSC亚群的发育机制提供了全新的认知视角，同时也为癌症治疗提供了潜在的新型生物标志物或治疗靶点。