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Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy

التفاصيل البيبلوغرافية
العنوان: Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy
المؤلفون: Anna Reustle, Moreno Di Marco, Carolin Meyerhoff, Annika Nelde, Juliane S. Walz, Stefan Winter, Siahei Kandabarau, Florian Büttner, Mathias Haag, Linus Backert, Daniel J. Kowalewski, Steffen Rausch, Jörg Hennenlotter, Viktoria Stühler, Marcus Scharpf, Falko Fend, Arnulf Stenzl, Hans-Georg Rammensee, Jens Bedke, Stefan Stevanović, Matthias Schwab, Elke Schaeffeler
المصدر: Genome Medicine
Genome Medicine, Vol 12, Iss 1, Pp 1-24 (2020)
سنة النشر: 2019
مصطلحات موضوعية: Adult, Male, lcsh:QH426-470, lcsh:Medicine, Kidney, Ligands, Lymphocyte Activation, Hypoxia-Inducible Factor-Proline Dioxygenases, HLA Antigens, Cell Line, Tumor, Cancer vaccine, Humans, HLA peptidome, Carcinoma, Renal Cell, Aged, Aged, 80 and over, Peptide vaccine, Binding Sites, Research, lcsh:R, ccRCC, Kidney cancer, Genomics, Middle Aged, Kidney Neoplasms, Peptide Fragments, Renal cell carcinoma, lcsh:Genetics, Ligandomics, Mutation, Female, Immunotherapy, Transcriptome, Protein Binding
الوصف: Background Clear cell renal cell carcinoma (ccRCC) is the dominant subtype of renal cancer. With currently available therapies, cure of advanced and metastatic ccRCC is achieved only in rare cases. Here, we developed a workflow integrating different -omics technologies to identify ccRCC-specific HLA-presented peptides as potential drug targets for ccRCC immunotherapy. Methods We analyzed HLA-presented peptides by MS-based ligandomics of 55 ccRCC tumors (cohort 1), paired non-tumor renal tissues, and 158 benign tissues from other organs. Pathways enriched in ccRCC compared to its cell type of origin were identified by transcriptome and gene set enrichment analyses in 51 tumor tissues of the same cohort. To retrieve a list of candidate targets with involvement in ccRCC pathogenesis, ccRCC-specific pathway genes were intersected with the source genes of tumor-exclusive peptides. The candidates were validated in an independent cohort from The Cancer Genome Atlas (TCGA KIRC, n = 452). DNA methylation (TCGA KIRC, n = 273), somatic mutations (TCGA KIRC, n = 392), and gene ontology (GO) and correlations with tumor metabolites (cohort 1, n = 30) and immune-oncological markers (cohort 1, n = 37) were analyzed to characterize regulatory and functional involvements. CD8+ T cell priming assays were used to identify immunogenic peptides. The candidate gene EGLN3 was functionally investigated in cell culture. Results A total of 34,226 HLA class I- and 19,325 class II-presented peptides were identified in ccRCC tissue, of which 443 class I and 203 class II peptides were ccRCC-specific and presented in ≥ 3 tumors. One hundred eighty-five of the 499 corresponding source genes were involved in pathways activated by ccRCC tumors. After validation in the independent cohort from TCGA, 113 final candidate genes remained. Candidates were involved in extracellular matrix organization, hypoxic signaling, immune processes, and others. Nine of the 12 peptides assessed by immunogenicity analysis were able to activate naïve CD8+ T cells, including peptides derived from EGLN3. Functional analysis of EGLN3 revealed possible tumor-promoting functions. Conclusions Integration of HLA ligandomics, transcriptomics, genetic, and epigenetic data leads to the identification of novel functionally relevant therapeutic targets for ccRCC immunotherapy. Validation of the identified targets is recommended to expand the treatment landscape of ccRCC.
تدمد: 1756-994X
URL الوصول: https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::b4428a09fe4a0ced29f3e80475121e94
https://pubmed.ncbi.nlm.nih.gov/32228647
حقوق: OPEN
رقم الأكسشن: edsair.pmid.dedup....b4428a09fe4a0ced29f3e80475121e94
قاعدة البيانات: OpenAIRE
الوصف
تدمد:1756994X