PMID- 37192158
OWN - NLM
STAT- MEDLINE
DCOM- 20230518
LR  - 20240123
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 120
IP  - 21
DP  - 2023 May 23
TI  - IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative 
      splicing.
PG  - e2221116120
LID - 10.1073/pnas.2221116120 [doi]
LID - e2221116120
AB  - 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.
FAU - Pan, Yang
AU  - Pan Y
AD  - Bioinformatics Interdepartmental Graduate Program, University of California, Los 
      Angeles, CA 90095.
AD  - Center for Computational and Genomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
FAU - Phillips, John W
AU  - Phillips JW
AD  - Department of Microbiology, Immunology and Molecular Genetics, University of 
      California, Los Angeles, CA 90095.
FAU - Zhang, Beatrice D
AU  - Zhang BD
AUID- ORCID: 0000-0003-1636-600X
AD  - Center for Computational and Genomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
FAU - Noguchi, Miyako
AU  - Noguchi M
AD  - Department of Microbiology, Immunology and Molecular Genetics, University of 
      California, Los Angeles, CA 90095.
FAU - Kutschera, Eric
AU  - Kutschera E
AUID- ORCID: 0000-0002-2160-1820
AD  - Center for Computational and Genomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
FAU - McLaughlin, Jami
AU  - McLaughlin J
AD  - Department of Microbiology, Immunology and Molecular Genetics, University of 
      California, Los Angeles, CA 90095.
FAU - Nesterenko, Pavlo A
AU  - Nesterenko PA
AUID- ORCID: 0000-0001-9841-8170
AD  - Molecular Biology Institute, University of California, Los Angeles, CA 90095.
FAU - Mao, Zhiyuan
AU  - Mao Z
AD  - Department of Molecular and Medical Pharmacology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Bangayan, Nathanael J
AU  - Bangayan NJ
AD  - Department of Molecular and Medical Pharmacology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Wang, Robert
AU  - Wang R
AD  - Center for Computational and Genomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
AD  - Graduate Group in Genomics and Computational Biology, University of Pennsylvania, 
      Philadelphia, PA 19104.
FAU - Tran, Wendy
AU  - Tran W
AD  - Department of Microbiology, Immunology and Molecular Genetics, University of 
      California, Los Angeles, CA 90095.
FAU - Yang, Harry T
AU  - Yang HT
AUID- ORCID: 0000-0001-9125-5962
AD  - Bioinformatics Interdepartmental Graduate Program, University of California, Los 
      Angeles, CA 90095.
FAU - Wang, Yuanyuan
AU  - Wang Y
AD  - Bioinformatics Interdepartmental Graduate Program, University of California, Los 
      Angeles, CA 90095.
AD  - Center for Computational and Genomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
FAU - Xu, Yang
AU  - Xu Y
AD  - Center for Computational and Genomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
AD  - Graduate Group in Genomics and Computational Biology, University of Pennsylvania, 
      Philadelphia, PA 19104.
FAU - Obusan, Matthew B
AU  - Obusan MB
AUID- ORCID: 0000-0002-9579-2308
AD  - Department of Microbiology, Immunology and Molecular Genetics, University of 
      California, Los Angeles, CA 90095.
FAU - Cheng, Donghui
AU  - Cheng D
AD  - Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, 
      University of California, Los Angeles, CA 90095.
FAU - Lee, Alex H
AU  - Lee AH
AD  - Department of Molecular and Medical Pharmacology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
AD  - Department of Neurosurgery, David Geffen School of Medicine, University of 
      California, Los Angeles, CA 90095.
FAU - Kadash-Edmondson, Kathryn E
AU  - Kadash-Edmondson KE
AD  - Center for Computational and Genomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
FAU - Champhekar, Ameya
AU  - Champhekar A
AD  - Division of Hematology-Oncology, Department of Medicine, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Puig-Saus, Cristina
AU  - Puig-Saus C
AUID- ORCID: 0000-0002-3014-3649
AD  - Division of Hematology-Oncology, Department of Medicine, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
AD  - Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 
      90095.
AD  - Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine, 
      University of California, Los Angeles, CA 90095.
FAU - Ribas, Antoni
AU  - Ribas A
AUID- ORCID: 0000-0003-3669-8458
AD  - Department of Molecular and Medical Pharmacology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
AD  - Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, 
      University of California, Los Angeles, CA 90095.
AD  - Division of Hematology-Oncology, Department of Medicine, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
AD  - Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 
      90095.
AD  - Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine, 
      University of California, Los Angeles, CA 90095.
AD  - Department of Surgery, David Geffen School of Medicine, University of California, 
      Los Angeles, CA 90095.
AD  - Department of Medicine, David Geffen School of Medicine, University of 
      California, Los Angeles, CA 90095.
FAU - Prins, Robert M
AU  - Prins RM
AD  - Department of Molecular and Medical Pharmacology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
AD  - Department of Neurosurgery, David Geffen School of Medicine, University of 
      California, Los Angeles, CA 90095.
AD  - Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 
      90095.
AD  - Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine, 
      University of California, Los Angeles, CA 90095.
FAU - Seet, Christopher S
AU  - Seet CS
AD  - Molecular Biology Institute, University of California, Los Angeles, CA 90095.
AD  - Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, 
      University of California, Los Angeles, CA 90095.
AD  - Division of Hematology-Oncology, Department of Medicine, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
AD  - Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 
      90095.
FAU - Crooks, Gay M
AU  - Crooks GM
AD  - Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, 
      University of California, Los Angeles, CA 90095.
AD  - Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 
      90095.
AD  - Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, 
      University of California, Los Angeles, CA 90095.
AD  - Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen 
      School of Medicine, University of California, Los Angeles, CA 90095.
FAU - Witte, Owen N
AU  - Witte ON
AUID- ORCID: 0000-0003-4461-4533
AD  - Department of Microbiology, Immunology and Molecular Genetics, University of 
      California, Los Angeles, CA 90095.
AD  - Molecular Biology Institute, University of California, Los Angeles, CA 90095.
AD  - Department of Molecular and Medical Pharmacology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
AD  - Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, 
      University of California, Los Angeles, CA 90095.
AD  - Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 
      90095.
AD  - Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine, 
      University of California, Los Angeles, CA 90095.
FAU - Xing, Yi
AU  - Xing Y
AD  - Center for Computational and Genomic Medicine, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
AD  - Department of Microbiology, Immunology and Molecular Genetics, University of 
      California, Los Angeles, CA 90095.
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, PA 19104.
AD  - Department of Biomedical and Health Informatics, The Children's Hospital of 
      Philadelphia, Philadelphia, PA 19104.
LA  - eng
GR  - P30 CA016042/CA/NCI NIH HHS/United States
GR  - P50 CA092131/CA/NCI NIH HHS/United States
GR  - R35 CA197633/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230516
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (RNA Precursors)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Peptides)
SB  - IM
MH  - Male
MH  - Humans
MH  - *RNA Precursors/metabolism
MH  - Alternative Splicing
MH  - Leukocytes, Mononuclear/metabolism
MH  - Receptors, Antigen, T-Cell
MH  - Epitopes, T-Lymphocyte
MH  - Immunotherapy
MH  - Antigens, Neoplasm
MH  - Peptides/metabolism
MH  - *Neoplasms/genetics/therapy
PMC - PMC10214192
OTO - NOTNLM
OT  - RNA splicing
OT  - T cell receptors
OT  - immunotherapy
COIS- Y.P., J.W.P., O.N.W., and Y. Xing are inventors on a provisional patent 
      application titled "Compositions and methods comprising splicing-derived antigens 
      for treating cancer." Y.P., A.H.L., R.M.P., and Y. Xing are inventors on a 
      provisional patent application titled "Identification of splicing-derived 
      antigens for treating cancer." Z.M., P.A.N., J.M., and O.N.W. are inventors on a 
      provisional patent application titled "Human T cell receptor pairs reactive with 
      HLA-A*02:01 restricted human prostatic acid phosphatase (PAP) epitopes." A.R. has 
      received honoraria from consulting with Amgen, Bristol-Myers Squibb, and Merck; 
      is or has been a member of the scientific advisory board and holds stock in 
      Advaxis, Appia, Apricity, Arcus, Compugen, CytomX, Highlight, ImaginAb, ImmPact, 
      ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, 
      Pluto, RAPT, Synthekine, and Tango; and has received research funding from 
      Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C) and 
      patent royalties from Arsenal Bio. C.S.S. and G.M.C. are cofounders of Pluto 
      Immunotherapeutics. O.N.W. currently has consulting, equity, and/or board 
      relationships with Trethera Corporation, Kronos Biosciences, Sofie Biosciences, 
      Breakthrough Properties, Vida Ventures, Nammi Therapeutics, Two River, Iconovir, 
      Appia BioSciences, Neogene Therapeutics, 76Bio, and Allogene Therapeutics. Y.Xing 
      is a scientific cofounder of Panorama Medicine and consulted for PACT Pharma. 
      None of these companies contributed to or directed any of the research reported 
      in this article. The remaining authors declare no competing interests. S.P.S. 
      coauthored a 2020 review with Y.P., K.E.K.-E., and Y. Xing.
EDAT- 2023/05/16 19:10
MHDA- 2023/05/18 06:42
PMCR- 2023/05/16
CRDT- 2023/05/16 13:23
PHST- 2023/05/18 06:42 [medline]
PHST- 2023/05/16 19:10 [pubmed]
PHST- 2023/05/16 13:23 [entrez]
PHST- 2023/05/16 00:00 [pmc-release]
AID - 202221116 [pii]
AID - 10.1073/pnas.2221116120 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2221116120. doi: 
      10.1073/pnas.2221116120. Epub 2023 May 16.