Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci

• Published in: Nature communications 2024-05, Vol.15 (1), p.4319-4319, Article 4319
• Main Authors: Miliotis, Christos, Ma, Yuling, Katopodi, Xanthi-Lida, Karagkouni, Dimitra, Kanata, Eleni, Mattioli, Kaia, Kalavros, Nikolas, Pita-Juárez, Yered H., Batalini, Felipe, Ramnarine, Varune R., Nanda, Shivani, Slack, Frank J., Vlachos, Ioannis S.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 3' Untranslated regions; 3' Untranslated Regions - genetics; 38/23; 38/47; 38/77; 38/90; 49/39; 49/88; 631/337/384/331; 631/67/1504/1829; 631/67/69; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Biomarkers; Cancer; Female; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Gene mapping; Genomes; Humanities and Social Sciences; Humans; Immune evasion; Immune system; Immunotherapy; Immunotherapy - methods; Lymphocytes; Lymphocytes T; Male; multidisciplinary; Mutation; PD-L1 protein; Phenotypes; Quantitative Trait Loci; Science; Science (multidisciplinary); Stomach Neoplasms - genetics; Stomach Neoplasms - immunology; T cell receptors; Tumor Escape - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48436-5

The landscape of non-coding mutations in cancer progression and immune evasion is largely unexplored. Here, we identify transcrptome-wide somatic and germline 3′ untranslated region (3′-UTR) variants from 375 gastric cancer patients from The Cancer Genome Atlas. By performing gene expression quantitative trait loci (eQTL) and immune landscape QTL (ilQTL) analysis, we discover 3′-UTR variants with cis effects on expression and immune landscape phenotypes, such as immune cell infiltration and T cell receptor diversity. Using a massively parallel reporter assay, we distinguish between causal and correlative effects of 3′-UTR eQTLs in immune-related genes. Our approach identifies numerous 3′-UTR eQTLs and ilQTLs, providing a unique resource for the identification of immunotherapeutic targets and biomarkers. A prioritized ilQTL variant signature predicts response to immunotherapy better than standard-of-care PD-L1 expression in independent patient cohorts, showcasing the untapped potential of non-coding mutations in cancer. The role of non-coding mutations in cancer progression and immune evasion needs to be further explored. Here, the authors investigate the potential of common somatic and germline 3′ untranslated region variants in predicting response to immunotherapy in gastric patients.