Ikeda Yuji, Kiyotani Kazuma, Yew Poh Yin, Sato Sho, Imai Yuichi, Yamaguchi Rui, Miyano Satoru, Fujiwara Keiichi, Hasegawa Kosei, Nakamura Yusuke
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 3501298, Japan.
Oncol Rep. 2017 May;37(5):2603-2610. doi: 10.3892/or.2017.5536. Epub 2017 Mar 29.
Immune microenvironment characterized by T cell clonality as well as expression signatures of immune-related genes in endometrial cancer tissues may play significant roles in clinical outcome of patients. We aimed to investigate the clinical significance of immune-related gene expression and TCR repertoire in endometrial cancer. Using total RNAs extracted from 32 endometrioid endometrial cancer cases, we performed quantitative real-time PCR to measure mRNA expression levels of immune-related genes including TRB, CD8, GZMA, HLA-A, CD11c and PD-L1. Higher mRNA expression levels of CD8 (P=0.039) and CD11c (P=0.046) in the 32 tissue samples were significantly associated with longer progression-free survival (PFS). Expression levels of CD8 (P<0.001) and CD11c (P=0.048) were also significantly associated with longer PFS in 540 cases in TCGA database. We also performed T cell receptor β (TCRβ) sequencing of tumor-infiltrating lymphocytes (TILs) on an Illumina MiSeq platform. To evaluate clonal expansion of TCRβ clonotypes, we adjusted the number of abundant TCRβ clonotypes by TRB mRNA expression levels and examined TCR clonality with the expression levels of immune-related genes and clinicopathological factors. The cases with high clonal T cell expansion along with high PD-L1 expression in cancer tissues was related to higher mRNA expression levels of CD8 (P<0.001), GZMA (P<0.001) and HLA-A (P=0.027), showed a significantly longer PFS (P=0.015), indicating a possibility that these parameters may serve as faborable prognostic factors. Considering clinical stage, mRNA expression of CD8 (P=0.037), GZMA (P=0.027) and HLA-A (P=0.022) was significantly higher in tumors at an early stage. Thus, we identified clinical and prognostic significance of immune microenvironment including the T cell clonality of TILs as well as PD-L1 and CD11c mRNA expression levels in endometrial cancer tissues.
以T细胞克隆性以及子宫内膜癌组织中免疫相关基因的表达特征为特点的免疫微环境，可能在患者的临床结局中发挥重要作用。我们旨在研究免疫相关基因表达和TCR库在子宫内膜癌中的临床意义。利用从32例子宫内膜样腺癌病例中提取的总RNA，我们进行了定量实时PCR，以测量包括TRB、CD8、GZMA、HLA - A、CD11c和PD - L1在内的免疫相关基因的mRNA表达水平。在这32个组织样本中，CD8（P = 0.039）和CD11c（P = 0.046）较高的mRNA表达水平与更长的无进展生存期（PFS）显著相关。在TCGA数据库的540例病例中，CD8（P < 0.001）和CD11c（P = 0.048）的表达水平也与更长的PFS显著相关。我们还在Illumina MiSeq平台上对肿瘤浸润淋巴细胞（TILs）进行了T细胞受体β（TCRβ）测序。为了评估TCRβ克隆型的克隆扩增，我们通过TRB mRNA表达水平调整了丰富的TCRβ克隆型数量，并检查了TCR克隆性与免疫相关基因的表达水平和临床病理因素的关系。癌症组织中具有高克隆性T细胞扩增以及高PD - L1表达的病例，与CD8（P < 0.001）、GZMA（P < 0.001）和HLA - A（P = 0.027）较高的mRNA表达水平相关，显示出显著更长的PFS（P = 0.015），表明这些参数有可能作为有利的预后因素。考虑到临床分期，早期肿瘤中CD8（P = 0.037）、GZMA（P = 0.027）和HLA - A（P = 0.022）的mRNA表达显著更高。因此，我们确定了免疫微环境的临床和预后意义，包括TILs的T细胞克隆性以及子宫内膜癌组织中PD - L1和CD11c mRNA表达水平。
