Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
13 06 2023
13 06 2023
Historique:
received:
24
10
2022
revised:
20
12
2022
accepted:
03
02
2023
medline:
14
6
2023
pubmed:
8
2
2023
entrez:
7
2
2023
Statut:
ppublish
Résumé
Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from noncanonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the immunogenicity of nonC tumor HLA-I ligands (nonC-TL) to better understand their contribution to cancer immunosurveillance and their therapeutic applicability. Peptides presented on HLA-I were identified in 9 patient-derived tumor cell lines from melanoma, gynecologic, and head and neck cancer through proteogenomics. A total of 507 candidate tumor antigens, including nonC-TL, neoantigens, cancer-germline, or melanocyte differentiation antigens, were tested for T-cell recognition of preexisting responses in patients with cancer. Donor peripheral blood lymphocytes (PBL) were in vitro sensitized against 170 selected nonC-TL to isolate antigen-specific T-cell receptors (TCR) and evaluate their therapeutic potential. We found no recognition of the 507 nonC-TL tested by autologous ex vivo expanded tumor-reactive T-cell cultures while the same cultures demonstrated reactivity to mutated, cancer-germline, or melanocyte differentiation antigens. However, in vitro sensitization of donor PBL against 170 selected nonC-TL, led to the identification of TCRs specific to three nonC-TL, two of which mapped to the 5' UTR regions of HOXC13 and ZKSCAN1, and one mapping to a noncoding spliced variant of C5orf22C. T cells targeting these nonC-TL recognized cancer cell lines naturally presenting their corresponding antigens. Expression of the three immunogenic nonC-TL was shared across tumor types and barely or not detected in normal cells. Our findings predict a limited contribution of nonC-TL to cancer immunosurveillance but demonstrate they may be attractive novel targets for widely applicable immunotherapies. See related commentary by Fox et al., p. 2173.
Identifiants
pubmed: 36749875
pii: 716448
doi: 10.1158/1078-0432.CCR-22-3298
pmc: PMC10261919
doi:
Substances chimiques
Ligands
0
Antigens, Neoplasm
0
Receptors, Antigen, T-Cell
0
Peptides
0
Types de publication
Editorial
Research Support, Non-U.S. Gov't
Comment
Langues
eng
Sous-ensembles de citation
IM
Pagination
2250-2265Commentaires et corrections
Type : CommentIn
Type : CommentOn
Type : CommentIn
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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