1. Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer.
- Author
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Merlotti A, Sadacca B, Arribas YA, Ngoma M, Burbage M, Goudot C, Houy A, Rocañín-Arjó A, Lalanne A, Seguin-Givelet A, Lefevre M, Heurtebise-Chrétien S, Baudon B, Oliveira G, Loew D, Carrascal M, Wu CJ, Lantz O, Stern MH, Girard N, Waterfall JJ, and Amigorena S
- Subjects
- Male, Humans, DNA Transposable Elements, CD8-Positive T-Lymphocytes pathology, Neoplasm Recurrence, Local genetics, Exons genetics, Antigens, Neoplasm genetics, Lung Neoplasms genetics, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology
- Abstract
Although most characterized tumor antigens are encoded by canonical transcripts (such as differentiation or tumor-testis antigens) or mutations (both driver and passenger mutations), recent results have shown that noncanonical transcripts including long noncoding RNAs and transposable elements (TEs) can also encode tumor-specific neo-antigens. Here, we investigate the presentation and immunogenicity of tumor antigens derived from noncanonical mRNA splicing events between coding exons and TEs. Comparing human non-small cell lung cancer (NSCLC) and diverse healthy tissues, we identified a subset of splicing junctions that is both tumor specific and shared across patients. We used HLA-I peptidomics to identify peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides were immunogenic in vitro, and CD8
+ T cells specific for junction-encoded epitopes were present in tumors and tumor-draining lymph nodes from patients with NSCLC. We conclude that noncanonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in patients with NSCLC.- Published
- 2023
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