Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China.
Department of Pathology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China.
Pathol Res Pract. 2022 Aug;236:153990. doi: 10.1016/j.prp.2022.153990. Epub 2022 Jun 18.
Lymphocyte activation gene-3 (LAG-3) is a novel molecule that participates in the immune escape of tumor cells and is a target for immunotherapy. However, the expression of LAG-3 in patients with endometrial cancer (EC) has not been comprehensively characterized.
We elucidated the expression of LAG-3 and investigated its correlation with clinicopathological parameters, ProMisE subtypes, CD8 T-cell infiltration and relapse-free survival (RFS) in a retrospective cohort of 421 patients with endometrial cancer.
Next-generation sequencing of the polymerase epsilon (POLE) and immunohistochemistry of mismatch repair (MMR)-related protein (MLH1, PMS2, MSH2, and MSH6), p53, CD8 and LAG-3 protein in whole sections were performed.
Positive LAG-3 was detected in tumor cells (TCs) and immune cells (ICs) in 31.6% (133/421) and 24.0% (101/421) of the patients, respectively. LAG-3 positivity in ICs was more common in high-grade, high-intermediate risk, high-risk, and advanced/metastatic subgroups and was relevant to lymphovascular space invasion, while that in TCs was more common in older individuals (≥54 years). LAG-3 expression was more prevalent in POLE ultramutated (POLEmut) and MMR-deficient (MMRd) EC than in p53-abnormal (p53abn) and p53-wild (p53wt) EC in TCs (34.4 % and 66.3% in POLEmut and MMRd versus 28.6% and 19.5% in p53abn and p53wt, P < 0.001) and ICs (78.1 % and 65.1% in POLEmut and MMRd versus 2.9% and 5.2% in p53abn and p53wt, P < 0.001). Positive expression of LAG-3 in TCs and ICs was associated with high levels of tumor-associated CD8 T-cell immune infiltration. Additionally, LAG-3 positivity in TCs was related to improved RFS.
This study suggests that immunotherapy targeting LAG-3 may play a role in EC patients with POLEmut or MMRd molecular markers. Positive LAG-3 expression in TCs may be a predictor of improved RFS.
淋巴细胞激活基因-3（LAG-3）是一种参与肿瘤细胞免疫逃逸的新型分子，是免疫治疗的靶点。然而，LAG-3 在子宫内膜癌（EC）患者中的表达尚未得到全面描述。
我们阐明了 LAG-3 的表达，并在一个回顾性的 421 名子宫内膜癌患者队列中研究了其与临床病理参数、ProMisE 亚型、CD8 T 细胞浸润和无复发生存率（RFS）的相关性。
对聚合酶 epsilon（POLE）进行下一代测序，并对整个切片进行错配修复（MMR）相关蛋白（MLH1、PMS2、MSH2 和 MSH6）、p53、CD8 和 LAG-3 蛋白的免疫组化检测。
在 421 名患者中，分别有 31.6%（133/421）和 24.0%（101/421）的患者肿瘤细胞（TCs）和免疫细胞（ICs）中检测到 LAG-3 阳性。ICs 中 LAG-3 阳性在高级别、高中危、高危和晚期/转移亚组中更为常见，与淋巴血管空间浸润相关，而 TCs 中 LAG-3 阳性在年龄较大的个体（≥54 岁）中更为常见。POLE 超突变（POLEmut）和 MMR 缺失（MMRd）EC 中 TCs（POLEmut 和 MMRd 中分别为 34.4%和 66.3%，p53abn 和 p53wt 中分别为 28.6%和 19.5%，P<0.001）和 ICs（POLEmut 和 MMRd 中分别为 78.1%和 65.1%，p53abn 和 p53wt 中分别为 2.9%和 5.2%，P<0.001）中 LAG-3 的表达比 p53 异常（p53abn）和 p53 野生型（p53wt）EC 更常见。TCs 和 ICs 中 LAG-3 的阳性表达与肿瘤相关 CD8 T 细胞免疫浸润水平较高相关。此外，TCs 中 LAG-3 阳性与改善 RFS 相关。
本研究提示针对 LAG-3 的免疫疗法可能在具有 POLEmut 或 MMRd 分子标志物的 EC 患者中发挥作用。TCs 中 LAG-3 的阳性表达可能是改善 RFS 的预测因子。
