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

Christos Miliotis, Yuling Ma, Xanthi-Lida Katopodi, Dimitra Karagkouni, Eleni Kanata, Kaia Mattioli, Nikolas Kalavros, Yered H. Pita-Juárez, Felipe Batalini, Varune R. Ramnarine, Shivani Nanda, Frank J. Slack () and Ioannis S. Vlachos ()
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Christos Miliotis: Harvard Medical School
Yuling Ma: Harvard Medical School
Xanthi-Lida Katopodi: Harvard Medical School
Dimitra Karagkouni: Harvard Medical School
Eleni Kanata: Harvard Medical School
Kaia Mattioli: Harvard Medical School
Nikolas Kalavros: Harvard Medical School
Yered H. Pita-Juárez: Harvard Medical School
Felipe Batalini: Harvard Medical School
Varune R. Ramnarine: Harvard Medical School
Shivani Nanda: Harvard Medical School
Frank J. Slack: Harvard Medical School
Ioannis S. Vlachos: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48436-5

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