Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Liver Cancer Translational Research Laboratory, BCLC, Liver Unit, CIBEREHD, IDIBAPS, Hospital Clinic, University of Barcelona, Catalonia, Spain.
Gastroenterology. 2017 Sep;153(3):812-826. doi: 10.1053/j.gastro.2017.06.007. Epub 2017 Jun 15.
BACKGROUND & AIMS: Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors.
We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumor samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune cell gene expression profiles with numbers of chromosomal aberrations (based on single-nucleotide polymorphism array) and mutations (exome sequence data).
We found approximately 25% of HCCs to have markers of an inflammatory response, with high expression levels of the CD274 molecule (programmed death-ligand 1) and programmed cell death 1, markers of cytolytic activity, and fewer chromosomal aberrations. We called this group of tumors the Immune class. It contained 2 subtypes, characterized by markers of an adaptive T-cell response or exhausted immune response. The exhausted immune response subclass expressed many genes regulated by transforming growth factor beta 1 that mediate immunosuppression. We did not observe any differences in numbers of mutations or expression of tumor antigens between the immune-specific class and other HCCs.
In an analysis of HCC samples from 956 patients, we found almost 25% to express markers of an inflammatory response. We identified 2 subclasses, characterized by adaptive or exhausted immune responses. These findings indicate that some HCCs might be susceptible to therapeutic agents designed to block the regulatory pathways in T cells, such as programmed death-ligand 1, programmed cell death 1, or transforming growth factor beta 1 inhibitors.
通过改变 T 细胞调节来诱导针对肿瘤的免疫反应的药物已延长了晚期肿瘤（如黑色素瘤或肺癌）患者的存活时间。我们旨在描述浸润肝细胞癌（HCC）的免疫细胞的分子特征，以确定这些类型的药物是否可能对肝肿瘤有效。
我们分析了 956 例患者的 HCC 样本。我们使用非负矩阵分解算法从肿瘤、基质和免疫细胞中分离基因表达谱。然后，我们分析了 HCC 肿瘤样本中炎症细胞的基因表达模式。我们在 228 例 HCC 样本的训练集中通过病理和免疫组化分析来确定免疫细胞浸润和免疫调节分子的存在，对表达模式进行了相关性分析。我们在 728 例肿瘤样本的验证集中验证了相关性。利用癌症基因组图谱中 190 个肿瘤的数据，我们将免疫细胞基因表达谱与染色体异常（基于单核苷酸多态性阵列）和突变（外显子组序列数据）的数量相关联。
我们发现大约 25%的 HCC 具有炎症反应的标志物，CD274 分子（程序性死亡配体 1）和程序性细胞死亡 1 的高表达水平，细胞溶解活性的标志物以及较少的染色体异常。我们将这群肿瘤称为免疫组。它包含 2 个亚型，特征是适应性 T 细胞反应或耗竭免疫反应的标志物。耗竭免疫反应亚类表达许多受转化生长因子β 1 调节的基因，这些基因介导免疫抑制。我们在免疫特异性组和其他 HCC 之间没有观察到突变数量或肿瘤抗原表达的任何差异。
在对 956 例患者的 HCC 样本进行分析后，我们发现近 25%的 HCC 表达炎症反应的标志物。我们确定了 2 个亚类，其特征是适应性或耗竭性免疫反应。这些发现表明，一些 HCC 可能易受旨在阻断 T 细胞调节途径的治疗药物的影响，例如程序性死亡配体 1、程序性细胞死亡 1 或转化生长因子β 1 抑制剂。
