Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Front Immunol. 2019 Sep 18;10:2243. doi: 10.3389/fimmu.2019.02243. eCollection 2019.
Myeloid-derived suppressor cells (MDSCs) are a major component of the immunosuppressive tumor microenvironment (TME) and have been recognized as a contributing factor to inflammation-related cancers. However, the molecular mechanisms of MDSCs accumulation and activation remain elusive. We previously showed that the proinflammatory molecule S100A9 in TME exerts a tumor-promoting effect in colorectal carcinoma (CRC). In this report, we investigated the effect and molecular mechanisms of S100A9 on the accumulation and immunosuppressive function of MDSCs in CRC. Elevated S100A9 and MDSCs were found in tumor tissue and peripheral blood from CRC patients. Circulating S100A9 and MDSCs were positively associated to each other, and both S100A9 and MDSCs were correlated to neoplastic progression. Using a CRC cell line LoVo-induced MDSCs model, we found that S100A9 stimulated chemotaxis and activation but not viability of MDSCs. Mechanistic studies demonstrated that activation of RAGE-mediated p38 MAPK and TLR4-mediated NF-κB signaling pathways were involved in S100A9-induced chemotaxis and MDSCs activation, respectively. Furthermore, ROC analysis showed that combination detection of S100A9 and MDSCs was superior to individual detection of these two factors for diagnosing CRC patients with advanced staging and lymphatic metastasis, which yielded an area under the ROC curve (AUC) of 0.92 with 86.7% sensitivity and 86.4% specificity, and an AUC of 0.82 with 75% sensitivity and 77.1% specificity, respectively. Collectively, our study suggests that the S100A9 plays a pivotal role in immunosuppressive TME by stimulating MDSCs chemotaxis and activation, and combination detection of S100A9 and MDSCs may serve as a potential marker for diagnosis of CRC progression.
髓系来源的抑制性细胞（MDSCs）是免疫抑制性肿瘤微环境（TME）的主要组成部分，已被认为是炎症相关癌症的一个促成因素。然而，MDSCs 积累和激活的分子机制仍不清楚。我们之前表明，TME 中的促炎分子 S100A9 在结直肠癌（CRC）中发挥促肿瘤作用。在本报告中，我们研究了 S100A9 对 CRC 中 MDSCs 积累和免疫抑制功能的影响及其分子机制。在 CRC 患者的肿瘤组织和外周血中发现了升高的 S100A9 和 MDSCs。循环 S100A9 和 MDSCs 彼此呈正相关，并且 S100A9 和 MDSCs 均与肿瘤进展相关。使用 CRC 细胞系 LoVo 诱导的 MDSCs 模型，我们发现 S100A9 刺激 MDSCs 的趋化和激活，但不影响其活力。机制研究表明，RAGE 介导的 p38 MAPK 和 TLR4 介导的 NF-κB 信号通路的激活参与了 S100A9 诱导的趋化和 MDSCs 激活。此外，ROC 分析表明，S100A9 和 MDSCs 的联合检测优于这两种因子的单独检测，可用于诊断具有晚期分期和淋巴转移的 CRC 患者，其 ROC 曲线下面积（AUC）为 0.92，灵敏度为 86.7%，特异性为 86.4%，AUC 为 0.82，灵敏度为 75%，特异性为 77.1%。总之，我们的研究表明，S100A9 通过刺激 MDSCs 的趋化和激活在免疫抑制性 TME 中发挥关键作用，并且 S100A9 和 MDSCs 的联合检测可能成为 CRC 进展诊断的潜在标志物。
