PXD041893

PXD041893 is an original dataset announced via ProteomeXchange.

Title	Adoptive T cell therapy targeting a widespread inducible product of aberrant mRNA translation
Description	Deregulated protein production by oncogenic pathways fuels tumor development. Consequently, the induction of tryptophan shortage by Indoleamine 2,3-Dioxygenase 1 (IDO1) enzyme, following interferon-gamma (IFNg) secretion by activated T cells, induces tryptophan to phenylalanine (W>F) substitutants1,2. These defective protein products are processed and presented on Human Leukocyte Antigen (HLA) molecules as neoepitopes. Here, we addressed the potential of substitutant neoepitopes to improve cancer immunotherapy. Adoptive cancer immunotherapy is an attractive treatment mode but suffers from the lack of widespread immunogenic targets, as somatic genetic aberrations in cancer are mostly private and counter-selected for strong immunogenicity3,4. Using immunopeptidomics, we identified IFNg-inducible common W>F substitutant neoepitopes presented on HLA-A*24:02, an abundant receptor allele in the Asian population that favors binding to peptides with phenylalanine in their sequence. TMBIM6W>F neoepitope from this list showed the broadest and second-highest expressed host gene in cancer transcriptome datasets. Therefore, we screened T cells and identified one TCR (TCRTMBIM6W>F.1) possessing high affinity and specificity towards TMBIM6W>F/HLA-A*24:02, compared to its wild-type counterpart. We further demonstrate that TCRTMBIM6W>F.1 T cells are reactivated by IFNg-mediated tryptophan-depleted cancer cells, provided they express HLA-A*24:02, TMBIM6, and IDO1, and are proficient in peptide presentation. Finally, in vivo xenograft experiments confirmed the ability of TCRTMBIM6W>F.1 T cells to suppress tumor progression. Thus, substitutant neoepitopes are widespread inducible products of aberrant mRNA translation that provide novel means to overcome current limitations in T-cell transfer therapy.
HostingRepository	PRIDE
AnnounceDate	2025-01-10
AnnouncementXML	Submission_2025-01-10_09:39:57.011.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Onno Bleijerveld
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-30 11:32:16	ID requested
⏵ 1	2025-01-10 09:39:57	announced

10.1016/J.IMMUNI.2024.12.004;

submitter keyword: substituants, adoptive T-cell therapy, mRNA translation,immunopeptidomics

Onno Bleijerveld
contact affiliation	NKI Proteomics Facility
contact email	o.bleijerveld@nki.nl
lab head
Onno Bleijerveld
contact affiliation	The Netherlands Cancer Institute
contact email	o.bleijerveld@nki.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041893
     1. Label: PRIDE project
     2. Name: Adoptive T cell therapy targeting a widespread inducible product of aberrant mRNA translation