Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics
peer-reviewed · Clinical Cancer Research · 2023
| Date | 2023-06-13 |
| Type | peer-reviewed |
| Venue | Clinical Cancer Research |
| Publisher | American Association for Cancer Research (AACR) |
| Contribution | downstream-application |
| DOI | 10.1158/1078-0432.ccr-22-3298 |
| Citations (OpenAlex) | 45 |
Abstract
Purpose 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. Experimental design 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. Results 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. Conclusions 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.
Methods and tools
- Noncanonical HLA-I tumour ligand immunogenicity: A de novo sequencing-based proteogenomic search found noncanonical HLA-I ligands in nine patient tumour cell lines; none was recognized by autologous T cells, though some elicited TCRs from donor blood.
Methods it uses
- PEAKS: Commercial DP-based de novo
- Peptide-PRISM: Identifies cryptic HLA-I peptides by matching the top de novo sequencing candidates for each spectrum against a six-frame translation of the genome and transcriptome, then scoring them in a stratified FDR; showed cryptic peptides are a substantial part of the HLA-I immunopeptidome.
Data deposited
- Immunogenicity of non-canonical HLA-I tumor ligands identified through proteogenomics — as deposited · PXD036856