Department of Gastroenterology, Singapore General Hospital, Singapore 169608, Republic of Singapore.
J Immunol. 2013 Jan 15;190(2):794-804. doi: 10.4049/jimmunol.1202088. Epub 2012 Dec 17.
Immune dysfunction may contribute to tumor progression in gastric cancer (GC) patients. One mechanism of immune dysfunction is the suppression of T cell activation and impairment of the efficacy of cancer immunotherapy by myeloid-derived suppressor cells (MDSCs). We assessed the phenotype and immunosuppressive function of MDSCs in GC patients. We further investigated the role of S100A8/A9 in GC and the relationship between S100A8/A9 and MDSC function. Lastly, the effect of MDSCs on survival rates and its potential as a prognostic factor in GC patients were investigated. MDSCs from PBMCs of GC patients were identified by comparing the expression of specific surface markers with PBMCs from healthy individuals. The ability of MDSCs to suppress T lymphocyte response and the effect of S100A8/A9 and RAGE blocking were tested in vitro by (autologous) MLR. GC patients had significantly more MDSCs than healthy individuals. These MDSCs suppressed both T lymphocyte proliferation and IFN-γ production and had high arginase-I expression. Levels of S100A8/A9 in plasma were higher in GC patients compared with healthy individuals, and they correlated with MDSC levels in the blood. Blocking of S100A8/A9 itself and the S100A8/A9 receptor RAGE on MDSCs from GC patients abrogated T cell effector function. We found that high levels of MDSCs correlated with more advanced cancer stage and with reduced survival (p = 0.006). S100A8/A9 has been identified as a potential target to modulate antitumor immunity by reversing MDSC-mediated immunosuppression.
免疫功能障碍可能导致胃癌（GC）患者的肿瘤进展。免疫功能障碍的一种机制是髓源抑制细胞（MDSC）抑制 T 细胞激活和损害癌症免疫疗法的疗效。我们评估了 GC 患者 MDSC 的表型和免疫抑制功能。我们进一步研究了 S100A8/A9 在 GC 中的作用以及 S100A8/A9 与 MDSC 功能之间的关系。最后，研究了 MDSC 对生存率的影响及其作为 GC 患者预后因素的潜力。通过与健康个体的 PBMC 比较，通过比较特定表面标志物的表达，从 GC 患者的 PBMC 中鉴定 MDSC。通过（自体）MLR 在体外测试 MDSC 抑制 T 淋巴细胞反应的能力以及 S100A8/A9 和 RAGE 阻断的作用。GC 患者的 MDSC 明显多于健康个体。这些 MDSC 抑制 T 淋巴细胞增殖和 IFN-γ产生，并具有高精氨酸酶-I 表达。与健康个体相比，GC 患者血浆中的 S100A8/A9 水平较高，并且与血液中的 MDSC 水平相关。阻断 GC 患者的 MDSC 上的 S100A8/A9 本身和 S100A8/A9 受体 RAGE 可消除 T 细胞效应功能。我们发现高水平的 MDSC 与更晚期的癌症阶段和降低的生存率相关（p = 0.006）。S100A8/A9 已被确定为通过逆转 MDSC 介导的免疫抑制来调节抗肿瘤免疫的潜在靶标。
