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Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics

2023; American Association for Cancer Research; Volume: 29; Issue: 12 Linguagem: Inglês

10.1158/1078-0432.ccr-22-3298

1557-3265

Maria Lozano-Rabella, Andrea García-Garijo, Jara Palomero, Anna Yuste-Estevanez, Florian Erhard, Roc Farriol-Duran, Juan Martín-Liberal, Maria Ochoa de Olza, Ignacio Matos, Jared J. Gartner, Michael Ghosh, Francesc Canals, August Vidal, Josep M. Piulats, Xavier Matías‐Guiu, Irene Braña, Eva Muñoz‐Couselo, Elena Garralda, Andreas Schlösser, Alena Gros,

CAR-T cell therapy research

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