Lymphocyte-activation gene 3 expression associates with poor prognosis and immunoevasive contexture in Epstein-Barr virus-positive and MLH1-defective gastric cancer patients
Lymphocyte-activation gene 3 expression associates with poor prognosis and immunoevasive contexture in Epstein-Barr virus-positive and MLH1-defective gastric cancer patients
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淋巴细胞激活基因 3 表达与 Epstein-Barr 病毒阳性和 MLH1 缺陷型胃癌患者的不良预后和免疫逃逸相关
DOI：
10.1002/ijc.33358
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发表时间：
2020-11-12
影响因子：
6.4
通讯作者：
Xu, Jiejie
中科院分区：
文献类型：
--
作者：
Lv, Kunpeng;Li, Ruochen;Xu, Jiejie
淋巴细胞激活基因3（LAG - 3）是一种跨膜免疫检查点，它通过抑制T细胞介导的抗肿瘤免疫来促进免疫逃逸。LAG - 3在胃癌中的作用鲜为人知。因此，我们评估了LAG - 3在胃癌中的临床意义。在我们的研究中，对来自中山医院的胃癌患者（n = 464）以及亚洲癌症研究小组的数据（n = 300）进行了分析。通过免疫组织化学检测胃癌中LAG - 3（+）细胞浸润及其他免疫微环境情况。采用Kaplan - Meier曲线和对数秩检验进行生存分析。肿瘤内LAG - 3（+）细胞主要聚集在爱泼斯坦 - 巴尔病毒（EBV）阳性（EBV亚型）和MLH1缺陷型（dMLH1亚型）胃癌中。此外，LAG - 3（+）细胞浸润与这两种胃癌亚型患者较差的临床结果密切相关。而且，我们发现肿瘤内LAG - 3（+）细胞高度浸润与一种免疫逃避微环境相关，其特征是在EBV/dMLH1亚型胃癌中γ - 干扰素（+）细胞和穿孔素 - 1（+）细胞减少，但调节性T细胞和M2样巨噬细胞增加。LAG - 3是一个不良预后因素，并且可能是EBV阳性和MLH1缺陷型胃癌的一个潜在免疫治疗靶点。
Lymphocyte activation gene 3 (LAG-3) is a transmembrane immune checkpoint that facilitates immune escape via suppressing T-cell-mediated anti-tumor immunity. The role of LAG-3 in gastric cancer is little known. Consequently, we assessed the clinical significance of LAG-3 in gastric cancer. In our study, patients with gastric cancer from Zhongshan Hospital (n = 464) and data from the Asian Cancer Research Group (n = 300) were analyzed. LAG-3(+) cell infiltration and other immune contexture in gastric cancer were detected by immunohistochemistry. Kaplan-Meier curves and log-rank test were used for survival analyses. Intratumoral LAG-3(+) cells mainly accumulated in Epstein-Barr virus (EBV)-positive (EBV subtype) and MLH1-defective (dMLH1 subtype) gastric cancer. Furthermore, LAG-3(+) cell infiltration was strongly associated with inferior clinical outcomes in patients with these two subtypes of gastric cancer. Moreover, we found intratumoral LAG-3(+) cell high infiltration was associated with an immunoevasive contexture featured by decreased IFN-gamma(+) cells and perforin-1(+) cells, but increased regulatory T cells and M2-like macrophages in EBV/dMLH1 subtype of gastric cancer. LAG-3 was a poor prognostic factor and might be a potential immunotherapeutic target in EBV-positive and MLH1-defective gastric cancer.