Noncoding regions are the main source of targetable tumor-specific antigens
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE127825 | GEO | 2019/11/20
REPOSITORIES: GEO
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Project description:Purpose: Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but very few of them have been identified. Therefore, the goal of this study was to develop a novel approach, combining RNA-Sequencing and mass spectrometry, to enlarge the landscape of actionable TSAs in seven human primary samples, namely 4 B-ALL and 3 lung tumor biopsies. Methods: We performed RNA-Sequencing on each primary tumor sample (unreplicated) with the Illumina HiSeq2000. Using those RNA-Sequencing data to build a global cancer database for each sample, we performed a transcriptomic-informed mass spectrometry analysis of their MHC I-associated peptides to identify TSAs. Results: We identified a total of 30 TSAs, 90% of which derived from allegedly non-coding regions and would have been missed by standard approaches. Moreover, most of these TSAs derived from non-mutated yet cancer-restricted transcripts that can be shared by multiple tumors. Conclusions: In conclusion, the strategy reported herein is readily applicable to human tumors and should considerably enlarge the landscape of actionable TSAs.
2018-10-18 | GSE113972 | GEO
Project description:Purpose: Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but very few of them have been identified. Therefore, the goal of this study was to develop a novel approach, combining RNA-Sequencing and mass spectrometry, to enlarge the landscape of actionable TSAs in two murine cell lines, namely EL4 and CT26 cells. Methods: We performed RNA-Sequencing on both tumor cell lines (unreplicated) as well as on the syngeneic mature medullary thymic epithelial cells (mTEChi, in triplicate), using either the Illumina HiSeq200 or the Illumina NextSeq 500. Using those RNA-Sequencing data to build a global cancer database for each tumor cell line, we performed a transcriptomic-informed mass spectrometry analysis of their MHC I-associated peptides to identify TSAs. Results: We identified a total of 21 TSAs, 90% of which derived from allegedly non-coding regions and would have been missed by standard approaches. Moreover, about 70% of these TSAs derived from non-mutated yet cancer-restricted transcripts (e.g., endogenous retroelements) that can be shared by multiple tumors. Conclusions: In conclusion, the strategy reported herein is readily applicable to human tumors and should considerably enlarge the landscape of actionable TSAs.
2018-10-18 | GSE111092 | GEO
Project description:Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but very few of them have been identified. We are using a proteogenomic approach, combining RNA-Sequencing and mass spectrometry, to discover TSAs. We performed RNA-Sequencing on human medullary thymic epithelial cells (mTECs) to use them as a "normal control" because they express most known genes and orchestrate T cell selection to induce central tolerance to MHC peptides coded by their vast transcriptome.
2019-11-20 | GSE127826 | GEO
Project description:High-grade serous ovarian cancer (HGSC), the principal cause of death from gynecological malignancies in the world, has not significantly benefited from advances in cancer immunotherapy. Although HGSC infiltration by lymphocytes correlates with superior survival, the nature of antigens that can elicit anti-HGSC immune responses is unknown. The goal of this study was to establish the global landscape of HGSC tumor-specific antigens (TSAs) using a mass spectrometry pipeline that interrogated all reading frames of all genomic regions. In 23 HGSC tumors, we identified 103 TSAs. Classic TSA discovery approaches focusing only on mutated exonic sequences would have uncovered only three of these TSAs. Other mutated TSAs resulted from out-of-frame exonic translation (n=2) or from noncoding sequences (n=7). One group of TSAs (n=91) derived from aberrantly expressed unmutated genomic sequences, which were not expressed in normal tissues. These aberrantly expressed TSAs (aeTSAs) originated primarily from non-exonic sequences, in particular intronic (29%) and intergenic (22%) sequences. Their expression was regulated at the transcriptional level by variations in gene copy number and DNA methylation. Although mutated TSAs were unique to individual tumors, aeTSAs were shared by a large proportion of HGSCs. Taking into account the frequency of aeTSA expression and HLA allele frequencies, we calculated that, in Caucasians, the median number of aeTSAs per tumor would be five. We conclude that, in view of their number and the fact that they are shared by many tumors, aeTSAs may be the most attractive targets for HGSC immunotherapy.
2020-02-08 | GSE131880 | GEO
Project description:MHC I-associated peptides (MAPs) presented at the surface of nucleated cells play a central role in CD8 T-cell immunosurveillance. MAPs presented by mature (i.e. MHC IIhi) medullary thymic epithelial cells (mTEChi) are essential to eliminate self-reactive CD8 T cells in a process called central tolerance. On tumor cells, MAPs that do not induce tolerance (i.e. non-tolerogenic MAPs), because absent from mTEChi or any other normal cells, are referred to as tumor-specific antigens (TSAs). Despite their clinical relevance, very few have been identified, even in highly mutated tumor types. Thus, we developed a novel proteogenomic workflow able to characterize the full TSA landscape of any tumor. Briefly, using RNA-seq data, we subtracted the mTEChi from the tumor signal to generate tumor-specific protein databases enriched in non-tolerogenic sequences. Using these databases to analyze the MAP repertoire of two murine cell lines (CT26 and EL4) sequenced by mass spectrometry, we identified a total of 21 TSAs, 90% of which derived from allegedly non-coding regions. Interestingly, our results highlighted that 70% of those TSAs derived from non-mutated yet tumor-restricted sequences, e.g. endogenous retroelements. Moreover, we showed that our approach is easily amenable to analyze human primary samples as we were able to identify TSAs in three lung tumor biopsies and four B-ALL specimens. Focusing on 5 TSAs, we demonstrated that both TSA expression and TSA-specific T-cell frequency in the pre-immune repertoire influenced the overall survival of pre-immunized tumor-bearing mice. In conclusion, this proof-of-concept study demonstrates that non-coding-derived TSAs are frequent and protective in vivo, while they could be shared by several individuals. Altogether, our findings will help expand the repertoire of human TSAs and facilitate their prioritization in the clinic.
2018-10-22 | PXD009752 | Pride
Project description:MHC I-associated peptides (MAPs) presented at the surface of nucleated cells play a central role in CD8 T-cell immunosurveillance. MAPs presented by mature (i.e. MHC IIhi) medullary thymic epithelial cells (mTEChi) are essential to eliminate self-reactive CD8 T cells in a process called central tolerance. On tumor cells, MAPs that do not induce tolerance (i.e. non-tolerogenic MAPs), because absent from mTEChi or any other normal cells, are referred to as tumor-specific antigens (TSAs). Despite their clinical relevance, very few have been identified, even in highly mutated tumor types. Thus, we developed a novel proteogenomic workflow able to characterize the full TSA landscape of any tumor. Briefly, using RNA-seq data, we subtracted the mTEChi from the tumor signal to generate tumor-specific protein databases enriched in non-tolerogenic sequences. Using these databases to analyze the MAP repertoire of two murine cell lines (CT26 and EL4) sequenced by mass spectrometry, we identified a total of 21 TSAs, 90% of which derived from allegedly non-coding regions. Interestingly, our results highlighted that 70% of those TSAs derived from non-mutated yet tumor-restricted sequences, e.g. endogenous retroelements. Moreover, we showed that our approach is easily amenable to analyze human primary samples as we were able to identify TSAs in three lung tumor biopsies and four B-ALL specimens. Focusing on 5 TSAs, we demonstrated that both TSA expression and TSA-specific T-cell frequency in the pre-immune repertoire influenced the overall survival of pre-immunized tumor-bearing mice. In conclusion, this proof-of-concept study demonstrates that non-coding-derived TSAs are frequent and protective in vivo, while they could be shared by several individuals. Altogether, our findings will help expand the repertoire of human TSAs and facilitate their prioritization in the clinic.
2018-10-22 | PXD009755 | Pride
Project description:MHC I-associated peptides (MAPs) presented at the surface of nucleated cells play a central role in CD8 T-cell immunosurveillance. MAPs presented by mature (i.e. MHC IIhi) medullary thymic epithelial cells (mTEChi) are essential to eliminate self-reactive CD8 T cells in a process called central tolerance. On tumor cells, MAPs that do not induce tolerance (i.e. non-tolerogenic MAPs), because absent from mTEChi or any other normal cells, are referred to as tumor-specific antigens (TSAs). Despite their clinical relevance, very few have been identified, even in highly mutated tumor types. Thus, we developed a novel proteogenomic workflow able to characterize the full TSA landscape of any tumor. Briefly, using RNA-seq data, we subtracted the mTEChi from the tumor signal to generate tumor-specific protein databases enriched in non-tolerogenic sequences. Using these databases to analyze the MAP repertoire of two murine cell lines (CT26 and EL4) sequenced by mass spectrometry, we identified a total of 21 TSAs, 90% of which derived from allegedly non-coding regions. Interestingly, our results highlighted that 70% of those TSAs derived from non-mutated yet tumor-restricted sequences, e.g. endogenous retroelements. Moreover, we showed that our approach is easily amenable to analyze human primary samples as we were able to identify TSAs in three lung tumor biopsies and four B-ALL specimens. Focusing on 5 TSAs, we demonstrated that both TSA expression and TSA-specific T-cell frequency in the pre-immune repertoire influenced the overall survival of pre-immunized tumor-bearing mice. In conclusion, this proof-of-concept study demonstrates that non-coding-derived TSAs are frequent and protective in vivo, while they could be shared by several individuals. Altogether, our findings will help expand the repertoire of human TSAs and facilitate their prioritization in the clinic.
2018-10-22 | PXD009749 | Pride
Project description:MHC I-associated peptides (MAPs) presented at the surface of nucleated cells play a central role in CD8 T-cell immunosurveillance. MAPs presented by mature (i.e. MHC IIhi) medullary thymic epithelial cells (mTEChi) are essential to eliminate self-reactive CD8 T cells in a process called central tolerance. On tumor cells, MAPs that do not induce tolerance (i.e. non-tolerogenic MAPs), because absent from mTEChi or any other normal cells, are referred to as tumor-specific antigens (TSAs). Despite their clinical relevance, very few have been identified, even in highly mutated tumor types. Thus, we developed a novel proteogenomic workflow able to characterize the full TSA landscape of any tumor. Briefly, using RNA-seq data, we subtracted the mTEChi from the tumor signal to generate tumor-specific protein databases enriched in non-tolerogenic sequences. Using these databases to analyze the MAP repertoire of two murine cell lines (CT26 and EL4) sequenced by mass spectrometry, we identified a total of 21 TSAs, 90% of which derived from allegedly non-coding regions. Interestingly, our results highlighted that 70% of those TSAs derived from non-mutated yet tumor-restricted sequences, e.g. endogenous retroelements. Moreover, we showed that our approach is easily amenable to analyze human primary samples as we were able to identify TSAs in three lung tumor biopsies and four B-ALL specimens. Focusing on 5 TSAs, we demonstrated that both TSA expression and TSA-specific T-cell frequency in the pre-immune repertoire influenced the overall survival of pre-immunized tumor-bearing mice. In conclusion, this proof-of-concept study demonstrates that non-coding-derived TSAs are frequent and protective in vivo, while they could be shared by several individuals. Altogether, our findings will help expand the repertoire of human TSAs and facilitate their prioritization in the clinic.
2018-10-22 | PXD009753 | Pride
Project description:MHC I-associated peptides (MAPs) presented at the surface of nucleated cells play a central role in CD8 T-cell immunosurveillance. MAPs presented by mature (i.e. MHC IIhi) medullary thymic epithelial cells (mTEChi) are essential to eliminate self-reactive CD8 T cells in a process called central tolerance. On tumor cells, MAPs that do not induce tolerance (i.e. non-tolerogenic MAPs), because absent from mTEChi or any other normal cells, are referred to as tumor-specific antigens (TSAs). Despite their clinical relevance, very few have been identified, even in highly mutated tumor types. Thus, we developed a novel proteogenomic workflow able to characterize the full TSA landscape of any tumor. Briefly, using RNA-seq data, we subtracted the mTEChi from the tumor signal to generate tumor-specific protein databases enriched in non-tolerogenic sequences. Using these databases to analyze the MAP repertoire of two murine cell lines (CT26 and EL4) sequenced by mass spectrometry, we identified a total of 21 TSAs, 90% of which derived from allegedly non-coding regions. Interestingly, our results highlighted that 70% of those TSAs derived from non-mutated yet tumor-restricted sequences, e.g. endogenous retroelements. Moreover, we showed that our approach is easily amenable to analyze human primary samples as we were able to identify TSAs in three lung tumor biopsies and four B-ALL specimens. Focusing on 5 TSAs, we demonstrated that both TSA expression and TSA-specific T-cell frequency in the pre-immune repertoire influenced the overall survival of pre-immunized tumor-bearing mice. In conclusion, this proof-of-concept study demonstrates that non-coding-derived TSAs are frequent and protective in vivo, while they could be shared by several individuals. Altogether, our findings will help expand the repertoire of human TSAs and facilitate their prioritization in the clinic.
2018-10-22 | PXD009751 | Pride
Project description:MHC I-associated peptides (MAPs) presented at the surface of nucleated cells play a central role in CD8 T-cell immunosurveillance. MAPs presented by mature (i.e. MHC IIhi) medullary thymic epithelial cells (mTEChi) are essential to eliminate self-reactive CD8 T cells in a process called central tolerance. On tumor cells, MAPs that do not induce tolerance (i.e. non-tolerogenic MAPs), because absent from mTEChi or any other normal cells, are referred to as tumor-specific antigens (TSAs). Despite their clinical relevance, very few have been identified, even in highly mutated tumor types. Thus, we developed a novel proteogenomic workflow able to characterize the full TSA landscape of any tumor. Briefly, using RNA-seq data, we subtracted the mTEChi from the tumor signal to generate tumor-specific protein databases enriched in non-tolerogenic sequences. Using these databases to analyze the MAP repertoire of two murine cell lines (CT26 and EL4) sequenced by mass spectrometry, we identified a total of 21 TSAs, 90% of which derived from allegedly non-coding regions. Interestingly, our results highlighted that 70% of those TSAs derived from non-mutated yet tumor-restricted sequences, e.g. endogenous retroelements. Moreover, we showed that our approach is easily amenable to analyze human primary samples as we were able to identify TSAs in three lung tumor biopsies and four B-ALL specimens. Focusing on 5 TSAs, we demonstrated that both TSA expression and TSA-specific T-cell frequency in the pre-immune repertoire influenced the overall survival of pre-immunized tumor-bearing mice. In conclusion, this proof-of-concept study demonstrates that non-coding-derived TSAs are frequent and protective in vivo, while they could be shared by several individuals. Altogether, our findings will help expand the repertoire of human TSAs and facilitate their prioritization in the clinic.
2018-10-22 | PXD009750 | Pride