Department of Oncology, Yantai Yuhuangding Hospital, Yantai, China.
Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Front Immunol. 2020 Sep 10;11:2048. doi: 10.3389/fimmu.2020.02048. eCollection 2020.
Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients. However, there is little information on CTLA4 and PD-1 expression levels and their clinical significance across diverse cancers. In this study, we addressed this question by analyzing PD-1 and CTLA4 levels in 33 different types of cancer along with their prognostic significance using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia datasets. Liver hepatocellular carcinoma (LIHC) patients receiving cytokine-induced killer cell (CIK) immunotherapy at Sun Yat-sen University cancer center were enrolled for survival analysis. The correlation between PD-1/CTLA4 expression and cancer immunity was also analyzed. The results showed that PD-1 and CTLA4 transcript levels varied across cancer cell lines, with aberrant expression detected in certain cancer types; Kaplan-Meier analysis with the Cox proportional hazards model showed that this was closely related to overall survival in breast invasive carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, acute myeloid leukemialymphoma, uterine corpus endometrial carcinoma, and uveal melanoma in TCGA. High serum PD-1 and CTLA4 levels predicted better survival in LIHC patients receiving CIK therapy. PD-1 and CTLA4 levels were found to be significantly correlated with the degree of tumor cell infiltration using Tumor Immune Estimation Resource, Estimating Relative Subsets of RNA Transcripts, and Estimation of Stromal and immune Cells in Malignant Tumor Tissues Using Expression Data as well as with tumor-infiltrating lymphocyte marker expression; they were also related to tumor mutation burden, microsatellite instability, mismatch repair, and the expression of DNA methyltransferases in some cancer types. Gene set enrichment analysis of 33 cancer types provided further evidence for associations between PD-1/CTLA4 levels and cancer development and immunocyte infiltration. Thus, PD-1 and CTLA4 play important roles in tumorigenesis and tumor immunity and can serve as prognostic biomarkers in different cancer types.
联合使用细胞毒性 T 淋巴细胞相关蛋白（CTLA）4 和程序性死亡（PD）-1 抑制剂在癌症患者中显示出疗效。然而，关于不同癌症中 CTLA4 和 PD-1 的表达水平及其临床意义的信息很少。在这项研究中，我们使用癌症基因组图谱（TCGA）和癌症细胞系百科全书数据集分析了 33 种不同类型癌症中的 PD-1 和 CTLA4 水平，并探讨了其预后意义。中山大学肿瘤中心接受细胞因子诱导的杀伤细胞（CIK）免疫治疗的肝癌（LIHC）患者被纳入生存分析。还分析了 PD-1/CTLA4 表达与癌症免疫之间的相关性。结果表明，PD-1 和 CTLA4 的转录水平在癌细胞系中存在差异，某些癌症类型存在异常表达；Kaplan-Meier 分析和 Cox 比例风险模型显示，这与 TCGA 中乳腺癌浸润性癌、胶质母细胞瘤多形性、头颈部鳞状细胞癌、急性髓样白血病/淋巴瘤、子宫体子宫内膜癌和葡萄膜黑色素瘤的总生存率密切相关。高血清 PD-1 和 CTLA4 水平预测接受 CIK 治疗的 LIHC 患者的生存更好。使用肿瘤免疫估计资源、相对 RNA 转录物子集的估计、使用表达数据估计恶性肿瘤组织中的基质和免疫细胞以及与肿瘤浸润淋巴细胞标志物表达，发现 PD-1 和 CTLA4 水平与肿瘤细胞浸润程度显著相关；它们还与肿瘤突变负担、微卫星不稳定性、错配修复以及某些癌症类型中 DNA 甲基转移酶的表达有关。33 种癌症的基因集富集分析进一步提供了 PD-1/CTLA4 水平与癌症发生和免疫细胞浸润之间关联的证据。因此，PD-1 和 CTLA4 在肿瘤发生和肿瘤免疫中发挥重要作用，并可作为不同癌症类型的预后生物标志物。
