外泌体 PD-L1 诱导的 MDSCs 扩增促进胃癌的进展。
The expansion of MDSCs induced by exosomal PD-L1 promotes the progression of gastric cancer.
机构信息
Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210029, Jiangsu, China.
No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
出版信息
J Transl Med. 2024 Sep 3;22(1):821. doi: 10.1186/s12967-024-05611-y.
BACKGROUND
Myeloid-derived suppressor cells (MDSCs) are the major factor in gastric cancer (GC) immune evasion. Nevertheless, the molecular process underlying the expansion of MDSCs induced by tumor-derived exosomes (TDEs) remains elusive.
METHODS
The levels of exosomal and soluble PD-L1 in ninety GC patients were examined via enzyme-linked immunosorbent assay (ELISA) to determine their prognostic value. To investigate the correlation between exosomal PD-L1 and MDSCs, the percentage of MDSCs in the peripheral blood of 57 GC patients was assessed via flow cytometry. Through ultracentrifugation, the exosomes were separated from the GC cell supernatant and detected via Western blotting, nanoparticle tracking analysis (NTA), and transmission electron microscopy (TEM). The function of exosomal PD-L1 in MDSCs was evaluated via immunofluorescence, Western blotting and flow cytometry in a GC cell-derived xenograft (CDX) model.
RESULTS
The overall survival (OS) of GC patients in the high exosomal PD-L1 group was significantly lower than that of patients in the low exosomal PD-L1 group (P = 0.0042); however, there was no significant correlation between soluble PD-L1 and OS in GC patients (P = 0.0501). Furthermore, we found that the expression of exosomal PD-L1 was positively correlated with the proportions of polymorphonuclear MDSCs (PMN-MDSCs, r = 0.4944, P < 0.001) and monocytic MDSCs (M-MDSCs, r = 0.3663, P = 0.005) in GC patients, indicating that exosomal PD-L1 might induce immune suppression by promoting the aggregation of MDSCs. In addition, we found that exosomal PD-L1 might stimulate MDSC proliferation by triggering the IL-6/STAT3 signaling pathway in vitro. The CDX model confirmed that exosomal PD-L1 could stimulate tumor development and MDSC amplification.
CONCLUSIONS
Exosomal PD-L1 has the potential to become a prognostic and diagnostic biomarker for GC patients. Mechanistically, MDSCs can be activated by exosomal PD-L1 through IL-6/STAT3 signaling and provide a new strategy against GC through the use of exosomal PD-L1 as a treatment target.
背景
髓源性抑制细胞（MDSCs）是胃癌（GC）免疫逃逸的主要因素。然而，肿瘤来源的外泌体（TDEs）诱导 MDSC 扩增的分子过程仍不清楚。
方法
通过酶联免疫吸附试验（ELISA）检测 90 例 GC 患者的外泌体和可溶性 PD-L1 水平，以确定其预后价值。为了研究外泌体 PD-L1 与 MDSCs 之间的相关性，通过流式细胞术评估 57 例 GC 患者外周血中 MDSCs 的百分比。通过超速离心从 GC 细胞上清液中分离出外泌体，并通过 Western blot、纳米颗粒跟踪分析（NTA）和透射电子显微镜（TEM）进行检测。在 GC 细胞衍生的异种移植（CDX）模型中，通过免疫荧光、Western blot 和流式细胞术评估外泌体 PD-L1 对 MDSCs 的作用。
结果
高外泌体 PD-L1 组 GC 患者的总生存期（OS）明显低于低外泌体 PD-L1 组（P=0.0042）；然而，GC 患者可溶性 PD-L1 与 OS 之间无显著相关性（P=0.0501）。此外，我们发现外泌体 PD-L1 的表达与 GC 患者中性粒细胞 MDSCs（PMN-MDSCs，r=0.4944，P<0.001）和单核细胞 MDSCs（M-MDSCs，r=0.3663，P=0.005）的比例呈正相关，表明外泌体 PD-L1 可能通过促进 MDSCs 的聚集来诱导免疫抑制。此外，我们发现外泌体 PD-L1 可能通过触发 IL-6/STAT3 信号通路在体外刺激 MDSC 增殖。CDX 模型证实外泌体 PD-L1 可刺激肿瘤发展和 MDSC 扩增。
结论
外泌体 PD-L1 有可能成为 GC 患者的预后和诊断生物标志物。从机制上讲，MDSCs 可以通过外泌体 PD-L1 激活 IL-6/STAT3 信号通路，通过将外泌体 PD-L1 作为治疗靶点提供一种新的 GC 治疗策略。
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