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; Ioannis S Vlachos

doi:10.1038/s41467-024-48436-5

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

Nat Commun. 2024 May 21;15(1):4319. doi: 10.1038/s41467-024-48436-5.

Authors

Christos Miliotis^{1

2}, Yuling Ma^{1

3}, Xanthi-Lida Katopodi¹, Dimitra Karagkouni^{1

3

4}, Eleni Kanata¹, Kaia Mattioli^{1

5}, Nikolas Kalavros^{1

3

6}, Yered H Pita-Juárez^{1

3}, Felipe Batalini^{1

7}, Varune R Ramnarine¹, Shivani Nanda^{1

3

4}, Frank J Slack^{8

9}, Ioannis S Vlachos^{10

11

12

13}

Affiliations

¹ Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
² Harvard Program in Virology, Harvard University Graduate School of Arts and Sciences, Boston, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Cancer Center & Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁵ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Spatial Technologies Unit, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁷ Division of Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ, USA.
⁸ Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
⁹ Cancer Center & Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
¹⁰ Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
¹² Cancer Center & Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
¹³ Spatial Technologies Unit, Beth Israel Deaconess Medical Center, Boston, MA, USA. [email protected].

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.

MeSH terms

3' Untranslated Regions* / genetics
B7-H1 Antigen / genetics
B7-H1 Antigen / metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
Immunotherapy / methods
Male
Mutation
Quantitative Trait Loci*
Stomach Neoplasms* / genetics
Stomach Neoplasms* / immunology
Tumor Escape* / genetics

Substances

CD274 protein, human

Abstract

MeSH terms

Substances

Grants and funding