Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Institute of Clinical Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China.
J Immunother. 2023 Jun 1;46(5):178-191. doi: 10.1097/CJI.0000000000000463. Epub 2023 Apr 27.
Although most endometrial cancer (EC) patients have a favorable prognosis, the overall survival (OS) of metastatic and recurrent EC could hardly be improved by the current chemoradiotherapy. We aimed to reveal the tumor microenvironment immune infiltration characteristics to elucidate the underlying mechanism of EC progression and guide clinical decisions. In the Cancer Genome Atlas (TCGA) cohort, Kaplan-Meier survival curves confirmed Tregs and CD8 T cells were prognosis-protective factors in OS of EC ( P <0.05). Weighted gene coexpression network analysis identified 2 gene modules closely correlated with Tregs and CD8 T-cell infiltration. We randomly split the TCGA EC cohort into the training and testing cohorts at a ratio of 7:3. An immune-related prognosis risk index (IRPRI), including NR3C1, E2F1, OTOG, TTK, PPP1R16B, and FOXP3, was established by univariate, Least Absolute Shrinkage and Selection Operator, and multivariate Cox regression with area under the curve >0.67. Distinct clinical, immune, and mutation characteristics existed between IRPRI groups by multiomics analysis. Cell proliferation and DNA damage repair-related pathways were activated, and immune-related pathways were inactivated in the IRPRI-high group. Furthermore, patients in the IRPRI-high group had lower tumor mutation burden, programmed death-ligand 1 expression, and Tumor Immune Dysfunction and Exclusion scores, indicating a poor response to immune checkpoint inhibitors therapy ( P <0.05), which was also validated in the TCGA testing cohort and independent cohorts, GSE78200, GSE115821, and GSE168204. Also, the higher mutation frequencies of BRCA1, BRCA2, and genes enrolled in homologous recombination repair in the IRPRI-low group predicted a good response to PARP inhibitors. Finally, a nomogram integrating the IRPRI group and prognosis significant clinicopathological factors for EC OS prediction was developed and validated with good discrimination and calibration.
尽管大多数子宫内膜癌（EC）患者预后良好，但转移性和复发性 EC 的总生存期（OS）几乎无法通过当前的放化疗得到改善。我们旨在揭示肿瘤微环境免疫浸润特征，以阐明 EC 进展的潜在机制并指导临床决策。在癌症基因组图谱（TCGA）队列中，Kaplan-Meier 生存曲线证实调节性 T 细胞（Tregs）和 CD8 T 细胞是 EC OS 的预后保护因素（P<0.05）。加权基因共表达网络分析确定了与 Tregs 和 CD8 T 细胞浸润密切相关的 2 个基因模块。我们将 TCGA EC 队列随机分为训练和测试队列，比例为 7:3。通过单变量、最小绝对收缩和选择算子以及多变量 Cox 回归，建立了一个包括 NR3C1、E2F1、OTOG、TTK、PPP1R16B 和 FOXP3 在内的免疫相关预后风险指数（IRPRI），曲线下面积（AUC）>0.67。通过多组学分析，IRPRI 组之间存在明显的临床、免疫和突变特征。IRPRI 高组中细胞增殖和 DNA 损伤修复相关途径被激活，而免疫相关途径被失活。此外，IRPRI 高组患者的肿瘤突变负担、程序性死亡配体 1 表达和肿瘤免疫功能障碍和排斥评分较低，提示对免疫检查点抑制剂治疗反应较差（P<0.05），这在 TCGA 测试队列和独立队列 GSE78200、GSE115821 和 GSE168204 中也得到了验证。此外，IRPRI 低组中 BRCA1、BRCA2 和同源重组修复相关基因的突变频率较高，预示着对 PARP 抑制剂有较好的反应。最后，我们建立并验证了一个整合 IRPRI 组和对 EC OS 预测有显著影响的预后临床病理因素的列线图，具有良好的区分度和校准度。
