Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450000, China.
Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450000, China.
Sci Rep. 2021 May 27;11(1):11220. doi: 10.1038/s41598-021-90794-3.
NK/T cell lymphoma (NKTCL) represents an aggressive lymphoid malignancy characterized by dismal prognosis. Immune-checkpoint blockade has shown promising efficacy in NKTCL. However, the molecular mechanisms underlying immune evasion in NKTCL have never been explored. Here, proteomic analysis was used to identify the differentially expressed proteins between NKTCL patients and healthy individuals. We found that S100A9, an immunosuppressive molecule, was much higher in NKTCL patients both in serum and tumor stroma. Elevated level of S100A9 was associated with advanced stage, poor overall response and early recurrence. Moreover, percentage of myeloid-derived suppressor cells (MDSCs) in peripheral blood was positively correlated with levels of S100A9. Low concentration of S100A9 promoted proliferation of NKTCL cells, while did not affect cell apoptosis and cell cycles. Furthermore, programmed death ligand 1 (PD-L1) expression on NKTCL cells was up-regulated by S100A9 through activation of ERK1/2 signaling. Inhibition of ERK1/2 signaling significantly decreased tumor growth and PD-L1 expression induced by S100A9. In conclusion, our research firstly identified S100A9 as an immune suppressor in the tumorigenesis of NKTCL via accumulation of MDSCs and upregulation of PD-L1 expression. S100A9 may serve as a potential target to increase the efficacy of immunotherapy in NKTCL.
NK/T 细胞淋巴瘤（NKTCL）是一种侵袭性淋巴恶性肿瘤，预后极差。免疫检查点阻断在 NKTCL 中显示出了有前景的疗效。然而，NKTCL 中免疫逃逸的分子机制从未被探索过。在这里，蛋白质组学分析被用于鉴定 NKTCL 患者和健康个体之间差异表达的蛋白。我们发现，S100A9，一种免疫抑制分子，在 NKTCL 患者的血清和肿瘤基质中均显著升高。S100A9 水平的升高与晚期、总体反应不良和早期复发相关。此外，外周血中髓系来源的抑制细胞（MDSCs）的比例与 S100A9 的水平呈正相关。S100A9 的低浓度促进了 NKTCL 细胞的增殖，而对细胞凋亡和细胞周期没有影响。此外，S100A9 通过激活 ERK1/2 信号通路上调了 NKTCL 细胞上的程序性死亡配体 1（PD-L1）的表达。ERK1/2 信号通路的抑制显著降低了 S100A9 诱导的肿瘤生长和 PD-L1 表达。总之，我们的研究首次通过 MDSCs 的积累和 PD-L1 表达的上调，确定了 S100A9 是 NKTCL 肿瘤发生中的一种免疫抑制因子。S100A9 可能成为增加 NKTCL 免疫治疗疗效的一个潜在靶点。
