Journal Article

Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures

Sander, Chris, Liu, Ming, Hakimi, A. Ari, Reuter, Victor E., Chen, Yingbei, Weinhold, Nils, Cheng, Emily H., Choueiri, Toni K., Drill, Esther, Hsieh, James J., Li, Ming O., de Velasco, Guillermo, Scheinberg, David A., Coleman, Jonathan A., Voss, Martin H., Russo, Paul, Van Allen, Eliezer M., Chan, Timothy A., Ostrovnaya, Irina, Miao, Diana, Lee, William, Luna, Augustin, Şenbabaoğlu, Yasin, Khalil, Danny N., Gejman, Ron S., Winer, Andrew G., Manley, Brandon J., Kaffenberger, Samuel D., Danilova, Ludmila

2016

Overview

Background Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types. Results We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8 + T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number. Conclusions Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.

• Publisher: BioMed Central,Springer Nature B.V
• Subject: Animal Genetics and Genomics / Antigen presentation / antigens / Bioinformatics / biomarkers / Biomedical and Life Sciences / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - immunology / Carcinoma, Renal Cell - therapy / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Clear cell-type renal cell carcinoma / Computer applications / Computer Simulation / Cytotoxicity / data collection / DNA methylation / Evolutionary Biology / Gene expression / Gene Expression Regulation, Neoplastic / genes / Genomes / Genomics / Helper cells / Human Genetics / Humans / immune response / Immunogenicity / Immunotherapy / Kidney cancer / Life Sciences / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Major histocompatibility complex / Melanoma / messenger RNA / Metastases / Microbial Genetics and Genomics / Mutation / Neoplasm Proteins - biosynthesis / Nucleotide Motifs - genetics / Peptides / Plant Genetics and Genomics / Prognosis / Proteomics / renal cell carcinoma / RNA, Messenger - biosynthesis / RNA, Messenger - genetics / T cell receptors / T-lymphocytes / transcriptomics / Tumor Microenvironment - genetics / Tumor Microenvironment - immunology / Tumor-infiltrating lymphocytes / Tumors