Jones Wendell D, Michener Chad M, Biscotti Charles, Braicu Iona, Sehouli Jalid, Ganapathi Mahrukh K, Ganapathi Ram N
Bioinformatics Group, Q2 Solutions - EA Genomics, 5927 S Miami Blvd, Morrisville, NC 27560, USA.
Division of Gynecologic Oncology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Cancers (Basel). 2020 Mar 7;12(3):620. doi: 10.3390/cancers12030620.
Immune cell infiltrates within the tumor microenvironment can influence treatment response and outcome in several cancers. In this study, we developed RNA-based immune signatures from pan-cancer analysis that could serve as potential markers across tumor types and tested them for association with outcome in high-grade serous ovarian cancer (HGSOC) and other female cancers. Pan-cancer RNA-Seq cluster analysis of immune-related gene expression profiles in The Cancer Genome Atlas (TCGA) from 29 different solid tumors (4446 specimens) identified distinct but concordant gene signatures. Among these immune signatures, Cytotoxic Lymphocyte Immune Signature (CLIS), T-cell trafficking (TCT), and the TCT to M2 tumor-associated macrophage (M2TAM) ratio (TCT:M2TAM) were significantly ( < 0.05) associated with overall survival (OS), using multivariable Cox proportional hazards regression models, in a discovery cohort and two independent validation cohorts of HGSOC patients. Notably, the TCT:M2TAM ratio was highly significant ( ≤ 0.000001) in two HGSOC cohorts. Immune signatures were also significant ( < 0.05) in the presence of tumor cytoreduction, mutation, and expression. Importantly, the CLIS and TCT signatures were also validated for prognostic significance ( < 0.05) in TCGA cohorts for endometrial and high tumor mutational burden (Hi-TMB) breast cancer. These immune signatures also have the potential for being predictive in other cancers and for patients following different treatment strategies.
肿瘤微环境中的免疫细胞浸润可影响多种癌症的治疗反应和预后。在本研究中，我们通过泛癌分析开发了基于RNA的免疫特征，这些特征可作为跨肿瘤类型的潜在标志物，并在高级别浆液性卵巢癌（HGSOC）和其他女性癌症中测试了它们与预后的相关性。对来自29种不同实体瘤（4446个样本）的癌症基因组图谱（TCGA）中免疫相关基因表达谱进行的泛癌RNA测序聚类分析确定了不同但一致的基因特征。在这些免疫特征中，使用多变量Cox比例风险回归模型，在HGSOC患者的一个发现队列和两个独立验证队列中，细胞毒性淋巴细胞免疫特征（CLIS）、T细胞转运（TCT）以及TCT与M2肿瘤相关巨噬细胞（M2TAM）的比例（TCT:M2TAM）与总生存期（OS）显著相关（<0.05）。值得注意的是，在两个HGSOC队列中，TCT:M2TAM比例具有高度显著性（≤0.000001）。在存在肿瘤细胞减灭、基因突变和基因表达的情况下，免疫特征也具有显著性（<0.05）。重要的是，CLIS和TCT特征在TCGA子宫内膜癌队列和高肿瘤突变负荷（Hi-TMB）乳腺癌队列中也被验证具有预后意义（<0.05）。这些免疫特征在其他癌症以及采用不同治疗策略的患者中也具有预测潜力。
