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IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing

Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), a computational platform capable of discovering AS-derived tumor antig...

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Autores principales: Pan, Yang, Phillips, John W., Zhang, Beatrice D., Noguchi, Miyako, Kutschera, Eric, McLaughlin, Jami, Nesterenko, Pavlo A., Mao, Zhiyuan, Bangayan, Nathanael J., Wang, Robert, Tran, Wendy, Yang, Harry T., Wang, Yuanyuan, Xu, Yang, Obusan, Matthew B., Cheng, Donghui, Lee, Alex H., Kadash-Edmondson, Kathryn E., Champhekar, Ameya, Puig-Saus, Cristina, Ribas, Antoni, Prins, Robert M., Seet, Christopher S., Crooks, Gay M., Witte, Owen N., Xing, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214192/
https://www.ncbi.nlm.nih.gov/pubmed/37192158
http://dx.doi.org/10.1073/pnas.2221116120
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author Pan, Yang
Phillips, John W.
Zhang, Beatrice D.
Noguchi, Miyako
Kutschera, Eric
McLaughlin, Jami
Nesterenko, Pavlo A.
Mao, Zhiyuan
Bangayan, Nathanael J.
Wang, Robert
Tran, Wendy
Yang, Harry T.
Wang, Yuanyuan
Xu, Yang
Obusan, Matthew B.
Cheng, Donghui
Lee, Alex H.
Kadash-Edmondson, Kathryn E.
Champhekar, Ameya
Puig-Saus, Cristina
Ribas, Antoni
Prins, Robert M.
Seet, Christopher S.
Crooks, Gay M.
Witte, Owen N.
Xing, Yi
author_facet Pan, Yang
Phillips, John W.
Zhang, Beatrice D.
Noguchi, Miyako
Kutschera, Eric
McLaughlin, Jami
Nesterenko, Pavlo A.
Mao, Zhiyuan
Bangayan, Nathanael J.
Wang, Robert
Tran, Wendy
Yang, Harry T.
Wang, Yuanyuan
Xu, Yang
Obusan, Matthew B.
Cheng, Donghui
Lee, Alex H.
Kadash-Edmondson, Kathryn E.
Champhekar, Ameya
Puig-Saus, Cristina
Ribas, Antoni
Prins, Robert M.
Seet, Christopher S.
Crooks, Gay M.
Witte, Owen N.
Xing, Yi
author_sort Pan, Yang
collection PubMed
description Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, we showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with “neoantigen-like” NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed in vitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derived TAs and expanding cancer immunotherapies.
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spelling pubmed-102141922023-05-27 IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing Pan, Yang Phillips, John W. Zhang, Beatrice D. Noguchi, Miyako Kutschera, Eric McLaughlin, Jami Nesterenko, Pavlo A. Mao, Zhiyuan Bangayan, Nathanael J. Wang, Robert Tran, Wendy Yang, Harry T. Wang, Yuanyuan Xu, Yang Obusan, Matthew B. Cheng, Donghui Lee, Alex H. Kadash-Edmondson, Kathryn E. Champhekar, Ameya Puig-Saus, Cristina Ribas, Antoni Prins, Robert M. Seet, Christopher S. Crooks, Gay M. Witte, Owen N. Xing, Yi Proc Natl Acad Sci U S A Biological Sciences Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, we showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with “neoantigen-like” NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed in vitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derived TAs and expanding cancer immunotherapies. National Academy of Sciences 2023-05-16 2023-05-23 /pmc/articles/PMC10214192/ /pubmed/37192158 http://dx.doi.org/10.1073/pnas.2221116120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Pan, Yang
Phillips, John W.
Zhang, Beatrice D.
Noguchi, Miyako
Kutschera, Eric
McLaughlin, Jami
Nesterenko, Pavlo A.
Mao, Zhiyuan
Bangayan, Nathanael J.
Wang, Robert
Tran, Wendy
Yang, Harry T.
Wang, Yuanyuan
Xu, Yang
Obusan, Matthew B.
Cheng, Donghui
Lee, Alex H.
Kadash-Edmondson, Kathryn E.
Champhekar, Ameya
Puig-Saus, Cristina
Ribas, Antoni
Prins, Robert M.
Seet, Christopher S.
Crooks, Gay M.
Witte, Owen N.
Xing, Yi
IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
title IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
title_full IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
title_fullStr IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
title_full_unstemmed IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
title_short IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
title_sort iris: discovery of cancer immunotherapy targets arising from pre-mrna alternative splicing
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214192/
https://www.ncbi.nlm.nih.gov/pubmed/37192158
http://dx.doi.org/10.1073/pnas.2221116120
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