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

Abstract 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Anna Reustle [verfasserIn] Moreno Di Marco [verfasserIn] Carolin Meyerhoff [verfasserIn] Annika Nelde [verfasserIn] Juliane S. Walz [verfasserIn] Stefan Winter [verfasserIn] Siahei Kandabarau [verfasserIn] Florian Büttner [verfasserIn] Mathias Haag [verfasserIn] Linus Backert [verfasserIn] Daniel J. Kowalewski [verfasserIn] Steffen Rausch [verfasserIn] Jörg Hennenlotter [verfasserIn] Viktoria Stühler [verfasserIn] Marcus Scharpf [verfasserIn] Falko Fend [verfasserIn] Arnulf Stenzl [verfasserIn] Hans-Georg Rammensee [verfasserIn] Jens Bedke [verfasserIn] Stefan Stevanović [verfasserIn] Matthias Schwab [verfasserIn] Elke Schaeffeler [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	ccRCC Renal cell carcinoma Ligandomics HLA peptidome Immunotherapy Peptide vaccine

Übergeordnetes Werk:	In: Genome Medicine - BMC, 2016, 12(2020), 1, Seite 24
Übergeordnetes Werk:	volume:12 ; year:2020 ; number:1 ; pages:24

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13073-020-00731-8

Katalog-ID:	DOAJ072697539

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520			\|a Abstract 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.
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650		4	\|a Renal cell carcinoma
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700	0		\|a Carolin Meyerhoff \|e verfasserin \|4 aut
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700	0		\|a Juliane S. Walz \|e verfasserin \|4 aut
700	0		\|a Stefan Winter \|e verfasserin \|4 aut
700	0		\|a Siahei Kandabarau \|e verfasserin \|4 aut
700	0		\|a Florian Büttner \|e verfasserin \|4 aut
700	0		\|a Mathias Haag \|e verfasserin \|4 aut
700	0		\|a Linus Backert \|e verfasserin \|4 aut
700	0		\|a Daniel J. Kowalewski \|e verfasserin \|4 aut
700	0		\|a Steffen Rausch \|e verfasserin \|4 aut
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700	0		\|a Viktoria Stühler \|e verfasserin \|4 aut
700	0		\|a Marcus Scharpf \|e verfasserin \|4 aut
700	0		\|a Falko Fend \|e verfasserin \|4 aut
700	0		\|a Arnulf Stenzl \|e verfasserin \|4 aut
700	0		\|a Hans-Georg Rammensee \|e verfasserin \|4 aut
700	0		\|a Jens Bedke \|e verfasserin \|4 aut
700	0		\|a Stefan Stevanović \|e verfasserin \|4 aut
700	0		\|a Matthias Schwab \|e verfasserin \|4 aut
700	0		\|a Elke Schaeffeler \|e verfasserin \|4 aut
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allfields	10.1186/s13073-020-00731-8 doi (DE-627)DOAJ072697539 (DE-599)DOAJfc55be784afc4fe685c251765eeb65fb DE-627 ger DE-627 rakwb eng QH426-470 Anna Reustle verfasserin aut Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. ccRCC Renal cell carcinoma Ligandomics HLA peptidome Immunotherapy Peptide vaccine Medicine R Genetics Moreno Di Marco verfasserin aut Carolin Meyerhoff verfasserin aut Annika Nelde verfasserin aut Juliane S. Walz verfasserin aut Stefan Winter verfasserin aut Siahei Kandabarau verfasserin aut Florian Büttner verfasserin aut Mathias Haag verfasserin aut Linus Backert verfasserin aut Daniel J. Kowalewski verfasserin aut Steffen Rausch verfasserin aut Jörg Hennenlotter verfasserin aut Viktoria Stühler verfasserin aut Marcus Scharpf verfasserin aut Falko Fend verfasserin aut Arnulf Stenzl verfasserin aut Hans-Georg Rammensee verfasserin aut Jens Bedke verfasserin aut Stefan Stevanović verfasserin aut Matthias Schwab verfasserin aut Elke Schaeffeler verfasserin aut In Genome Medicine BMC, 2016 12(2020), 1, Seite 24 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:12 year:2020 number:1 pages:24 https://doi.org/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/article/fc55be784afc4fe685c251765eeb65fb kostenfrei http://link.springer.com/article/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 24
spelling	10.1186/s13073-020-00731-8 doi (DE-627)DOAJ072697539 (DE-599)DOAJfc55be784afc4fe685c251765eeb65fb DE-627 ger DE-627 rakwb eng QH426-470 Anna Reustle verfasserin aut Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. ccRCC Renal cell carcinoma Ligandomics HLA peptidome Immunotherapy Peptide vaccine Medicine R Genetics Moreno Di Marco verfasserin aut Carolin Meyerhoff verfasserin aut Annika Nelde verfasserin aut Juliane S. Walz verfasserin aut Stefan Winter verfasserin aut Siahei Kandabarau verfasserin aut Florian Büttner verfasserin aut Mathias Haag verfasserin aut Linus Backert verfasserin aut Daniel J. Kowalewski verfasserin aut Steffen Rausch verfasserin aut Jörg Hennenlotter verfasserin aut Viktoria Stühler verfasserin aut Marcus Scharpf verfasserin aut Falko Fend verfasserin aut Arnulf Stenzl verfasserin aut Hans-Georg Rammensee verfasserin aut Jens Bedke verfasserin aut Stefan Stevanović verfasserin aut Matthias Schwab verfasserin aut Elke Schaeffeler verfasserin aut In Genome Medicine BMC, 2016 12(2020), 1, Seite 24 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:12 year:2020 number:1 pages:24 https://doi.org/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/article/fc55be784afc4fe685c251765eeb65fb kostenfrei http://link.springer.com/article/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 24
allfields_unstemmed	10.1186/s13073-020-00731-8 doi (DE-627)DOAJ072697539 (DE-599)DOAJfc55be784afc4fe685c251765eeb65fb DE-627 ger DE-627 rakwb eng QH426-470 Anna Reustle verfasserin aut Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. ccRCC Renal cell carcinoma Ligandomics HLA peptidome Immunotherapy Peptide vaccine Medicine R Genetics Moreno Di Marco verfasserin aut Carolin Meyerhoff verfasserin aut Annika Nelde verfasserin aut Juliane S. Walz verfasserin aut Stefan Winter verfasserin aut Siahei Kandabarau verfasserin aut Florian Büttner verfasserin aut Mathias Haag verfasserin aut Linus Backert verfasserin aut Daniel J. Kowalewski verfasserin aut Steffen Rausch verfasserin aut Jörg Hennenlotter verfasserin aut Viktoria Stühler verfasserin aut Marcus Scharpf verfasserin aut Falko Fend verfasserin aut Arnulf Stenzl verfasserin aut Hans-Georg Rammensee verfasserin aut Jens Bedke verfasserin aut Stefan Stevanović verfasserin aut Matthias Schwab verfasserin aut Elke Schaeffeler verfasserin aut In Genome Medicine BMC, 2016 12(2020), 1, Seite 24 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:12 year:2020 number:1 pages:24 https://doi.org/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/article/fc55be784afc4fe685c251765eeb65fb kostenfrei http://link.springer.com/article/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 24
allfieldsGer	10.1186/s13073-020-00731-8 doi (DE-627)DOAJ072697539 (DE-599)DOAJfc55be784afc4fe685c251765eeb65fb DE-627 ger DE-627 rakwb eng QH426-470 Anna Reustle verfasserin aut Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. ccRCC Renal cell carcinoma Ligandomics HLA peptidome Immunotherapy Peptide vaccine Medicine R Genetics Moreno Di Marco verfasserin aut Carolin Meyerhoff verfasserin aut Annika Nelde verfasserin aut Juliane S. Walz verfasserin aut Stefan Winter verfasserin aut Siahei Kandabarau verfasserin aut Florian Büttner verfasserin aut Mathias Haag verfasserin aut Linus Backert verfasserin aut Daniel J. Kowalewski verfasserin aut Steffen Rausch verfasserin aut Jörg Hennenlotter verfasserin aut Viktoria Stühler verfasserin aut Marcus Scharpf verfasserin aut Falko Fend verfasserin aut Arnulf Stenzl verfasserin aut Hans-Georg Rammensee verfasserin aut Jens Bedke verfasserin aut Stefan Stevanović verfasserin aut Matthias Schwab verfasserin aut Elke Schaeffeler verfasserin aut In Genome Medicine BMC, 2016 12(2020), 1, Seite 24 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:12 year:2020 number:1 pages:24 https://doi.org/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/article/fc55be784afc4fe685c251765eeb65fb kostenfrei http://link.springer.com/article/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 24
allfieldsSound	10.1186/s13073-020-00731-8 doi (DE-627)DOAJ072697539 (DE-599)DOAJfc55be784afc4fe685c251765eeb65fb DE-627 ger DE-627 rakwb eng QH426-470 Anna Reustle verfasserin aut Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. ccRCC Renal cell carcinoma Ligandomics HLA peptidome Immunotherapy Peptide vaccine Medicine R Genetics Moreno Di Marco verfasserin aut Carolin Meyerhoff verfasserin aut Annika Nelde verfasserin aut Juliane S. Walz verfasserin aut Stefan Winter verfasserin aut Siahei Kandabarau verfasserin aut Florian Büttner verfasserin aut Mathias Haag verfasserin aut Linus Backert verfasserin aut Daniel J. Kowalewski verfasserin aut Steffen Rausch verfasserin aut Jörg Hennenlotter verfasserin aut Viktoria Stühler verfasserin aut Marcus Scharpf verfasserin aut Falko Fend verfasserin aut Arnulf Stenzl verfasserin aut Hans-Georg Rammensee verfasserin aut Jens Bedke verfasserin aut Stefan Stevanović verfasserin aut Matthias Schwab verfasserin aut Elke Schaeffeler verfasserin aut In Genome Medicine BMC, 2016 12(2020), 1, Seite 24 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:12 year:2020 number:1 pages:24 https://doi.org/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/article/fc55be784afc4fe685c251765eeb65fb kostenfrei http://link.springer.com/article/10.1186/s13073-020-00731-8 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 24
language	English
source	In Genome Medicine 12(2020), 1, Seite 24 volume:12 year:2020 number:1 pages:24
sourceStr	In Genome Medicine 12(2020), 1, Seite 24 volume:12 year:2020 number:1 pages:24
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	ccRCC Renal cell carcinoma Ligandomics HLA peptidome Immunotherapy Peptide vaccine Medicine R Genetics
isfreeaccess_bool	true
container_title	Genome Medicine
authorswithroles_txt_mv	Anna Reustle @@aut@@ Moreno Di Marco @@aut@@ Carolin Meyerhoff @@aut@@ Annika Nelde @@aut@@ Juliane S. Walz @@aut@@ Stefan Winter @@aut@@ Siahei Kandabarau @@aut@@ Florian Büttner @@aut@@ Mathias Haag @@aut@@ Linus Backert @@aut@@ Daniel J. Kowalewski @@aut@@ Steffen Rausch @@aut@@ Jörg Hennenlotter @@aut@@ Viktoria Stühler @@aut@@ Marcus Scharpf @@aut@@ Falko Fend @@aut@@ Arnulf Stenzl @@aut@@ Hans-Georg Rammensee @@aut@@ Jens Bedke @@aut@@ Stefan Stevanović @@aut@@ Matthias Schwab @@aut@@ Elke Schaeffeler @@aut@@
publishDateDaySort_date	2020-01-01T00:00:00Z
hierarchy_top_id	594424275
id	DOAJ072697539
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ072697539</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230501172233.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230228s2020 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13073-020-00731-8</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ072697539</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJfc55be784afc4fe685c251765eeb65fb</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QH426-470</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Anna Reustle</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract 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. 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callnumber-first	Q - Science
author	Anna Reustle
spellingShingle	Anna Reustle misc QH426-470 misc ccRCC misc Renal cell carcinoma misc Ligandomics misc HLA peptidome misc Immunotherapy misc Peptide vaccine misc Medicine misc R misc Genetics Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy
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topic_title	QH426-470 Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy ccRCC Renal cell carcinoma Ligandomics HLA peptidome Immunotherapy Peptide vaccine
topic	misc QH426-470 misc ccRCC misc Renal cell carcinoma misc Ligandomics misc HLA peptidome misc Immunotherapy misc Peptide vaccine misc Medicine misc R misc Genetics
topic_unstemmed	misc QH426-470 misc ccRCC misc Renal cell carcinoma misc Ligandomics misc HLA peptidome misc Immunotherapy misc Peptide vaccine misc Medicine misc R misc Genetics
topic_browse	misc QH426-470 misc ccRCC misc Renal cell carcinoma misc Ligandomics misc HLA peptidome misc Immunotherapy misc Peptide vaccine misc Medicine misc R misc Genetics
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title	Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy
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title_full	Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy
author_sort	Anna Reustle
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author_browse	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
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title_sort	integrative -omics and hla-ligandomics analysis to identify novel drug targets for ccrcc immunotherapy
callnumber	QH426-470
title_auth	Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy
abstract	Abstract 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.
abstractGer	Abstract 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.
abstract_unstemmed	Abstract 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.
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title_short	Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy
url	https://doi.org/10.1186/s13073-020-00731-8 https://doaj.org/article/fc55be784afc4fe685c251765eeb65fb http://link.springer.com/article/10.1186/s13073-020-00731-8 https://doaj.org/toc/1756-994X
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up_date	2024-07-03T13:33:47.584Z
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fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ072697539</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230501172233.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230228s2020 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13073-020-00731-8</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ072697539</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJfc55be784afc4fe685c251765eeb65fb</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QH426-470</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Anna Reustle</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract 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. 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Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy

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