Dannenfelser Ruth, Nome Marianne, Tahiri Andliena, Ursini-Siegel Josie, Vollan Hans Kristian Moen, Haakensen Vilde D, Helland Åslaug, Naume Bjørn, Caldas Carlos, Børresen-Dale Anne-Lise, Kristensen Vessela N, Troyanskaya Olga G
Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
Oncotarget. 2017 Jul 7;8(34):57121-57133. doi: 10.18632/oncotarget.19078. eCollection 2017 Aug 22.
The tumor microenvironment is now widely recognized for its role in tumor progression, treatment response, and clinical outcome. The intratumoral immunological landscape, in particular, has been shown to exert both pro-tumorigenic and anti-tumorigenic effects. Identifying immunologically active or silent tumors may be an important indication for administration of therapy, and detecting early infiltration patterns may uncover factors that contribute to early risk. Thus far, direct detailed studies of the cell composition of tumor infiltration have been limited; with some studies giving approximate quantifications using immunohistochemistry and other small studies obtaining detailed measurements by isolating cells from excised tumors and sorting them using flow cytometry. Herein we utilize a machine learning based approach to identify lymphocyte markers with which we can quantify the presence of B cells, cytotoxic T-lymphocytes, T-helper 1, and T-helper 2 cells in any gene expression data set and apply it to studies of breast tissue. By leveraging over 2,100 samples from existing large scale studies, we are able to find an inherent cell heterogeneity in clinically characterized immune infiltrates, a strong link between estrogen receptor activity and infiltration in normal and tumor tissues, changes with genomic complexity, and identify characteristic differences in lymphocyte expression among molecular groupings. With our extendable methodology for capturing cell type specific signal we systematically studied immune infiltration in breast cancer, finding an inverse correlation between beneficial lymphocyte infiltration and estrogen receptor activity in normal breast tissue and reduced infiltration in estrogen receptor negative tumors with high genomic complexity.
肿瘤微环境在肿瘤进展、治疗反应和临床结果中的作用现已得到广泛认可。特别是肿瘤内的免疫格局已被证明具有促肿瘤和抗肿瘤作用。识别免疫活性或免疫沉默的肿瘤可能是进行治疗的重要指征,而检测早期浸润模式可能会发现导致早期风险的因素。到目前为止,对肿瘤浸润细胞组成的直接详细研究一直有限;一些研究使用免疫组织化学进行大致定量,其他一些小型研究则通过从切除的肿瘤中分离细胞并使用流式细胞术对其进行分选来获得详细测量。在此,我们利用基于机器学习的方法来识别淋巴细胞标志物,通过这些标志物我们可以在任何基因表达数据集中量化B细胞、细胞毒性T淋巴细胞、辅助性T细胞1和辅助性T细胞2的存在,并将其应用于乳腺组织研究。通过利用来自现有大规模研究的2100多个样本,我们能够发现临床特征性免疫浸润中固有的细胞异质性、雌激素受体活性与正常和肿瘤组织浸润之间的紧密联系、随基因组复杂性的变化,并识别分子分组之间淋巴细胞表达的特征差异。通过我们用于捕获细胞类型特异性信号的可扩展方法,我们系统地研究了乳腺癌中的免疫浸润,发现正常乳腺组织中有益的淋巴细胞浸润与雌激素受体活性呈负相关,而在基因组复杂性高的雌激素受体阴性肿瘤中浸润减少。