Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1785047786555703296 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10214192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT panyang irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT phillipsjohnw irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT zhangbeatriced irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT noguchimiyako irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT kutscheraeric irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT mclaughlinjami irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT nesterenkopavloa irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT maozhiyuan irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT bangayannathanaelj irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT wangrobert irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT tranwendy irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT yangharryt irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT wangyuanyuan irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT xuyang irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT obusanmatthewb irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT chengdonghui irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT leealexh irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT kadashedmondsonkathryne irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT champhekarameya irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT puigsauscristina irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT ribasantoni irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT prinsrobertm irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT seetchristophers irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT crooksgaym irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT witteowenn irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing AT xingyi irisdiscoveryofcancerimmunotherapytargetsarisingfrompremrnaalternativesplicing |