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

Author

Listed:
  • Christos Miliotis

    (Harvard Medical School
    Harvard University Graduate School of Arts and Sciences)

  • Yuling Ma

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Xanthi-Lida Katopodi

    (Harvard Medical School)

  • Dimitra Karagkouni

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Eleni Kanata

    (Harvard Medical School)

  • Kaia Mattioli

    (Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Nikolas Kalavros

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Beth Israel Deaconess Medical Center)

  • Yered H. Pita-Juárez

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Felipe Batalini

    (Harvard Medical School
    Mayo Clinic)

  • Varune R. Ramnarine

    (Harvard Medical School)

  • Shivani Nanda

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Frank J. Slack

    (Harvard Medical School
    Harvard Medical School)

  • Ioannis S. Vlachos

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School
    Beth Israel Deaconess Medical Center)

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.

Suggested Citation

  • 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 Nan, 2024. "Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48436-5
    DOI: 10.1038/s41467-024-48436-5
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