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

Autor: Reustle A; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany., Di Marco M; Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany., Meyerhoff C; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany., Nelde A; Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany.; German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany., Walz JS; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany.; German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany.; iFIT Cluster of Excellence (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany., Winter S; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany., Kandabarau S; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany., Büttner F; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany., Haag M; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany., Backert L; Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany., Kowalewski DJ; Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany., Rausch S; Department of Urology, University Hospital Tuebingen, Tuebingen, Germany., Hennenlotter J; Department of Urology, University Hospital Tuebingen, Tuebingen, Germany., Stühler V; Department of Urology, University Hospital Tuebingen, Tuebingen, Germany., Scharpf M; Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany., Fend F; Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany., Stenzl A; Department of Urology, University Hospital Tuebingen, Tuebingen, Germany., Rammensee HG; Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.; German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany.; iFIT Cluster of Excellence (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany., Bedke J; Department of Urology, University Hospital Tuebingen, Tuebingen, Germany., Stevanović S; Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.; German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany.; iFIT Cluster of Excellence (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany., Schwab M; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. matthias.schwab@ikp-stuttgart.de.; University of Tuebingen, Tuebingen, Germany. matthias.schwab@ikp-stuttgart.de.; German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany. matthias.schwab@ikp-stuttgart.de.; iFIT Cluster of Excellence (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany. matthias.schwab@ikp-stuttgart.de.; Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany. matthias.schwab@ikp-stuttgart.de., Schaeffeler E; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany.; iFIT Cluster of Excellence (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2020 Mar 30; Vol. 12 (1), pp. 32. Date of Electronic Publication: 2020 Mar 30.
DOI: 10.1186/s13073-020-00731-8
Abstrakt: 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.
Databáze: MEDLINE
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