IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48436-5.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48436-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-48436-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Keyong Sun & Runda Xu & Fuhai Ma & Naixue Yang & Yang Li & Xiaofeng Sun & Peng Jin & Wenzhe Kang & Lemei Jia & Jianping Xiong & Haitao Hu & Yantao Tian & Xun Lan, 2022. "scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Nick Patterson & Alkes L Price & David Reich, 2006. "Population Structure and Eigenanalysis," PLOS Genetics, Public Library of Science, vol. 2(12), pages 1-20, December.
    3. Robert T. Manguso & Hans W. Pope & Margaret D. Zimmer & Flavian D. Brown & Kathleen B. Yates & Brian C. Miller & Natalie B. Collins & Kevin Bi & Martin W. LaFleur & Vikram R. Juneja & Sarah A. Weiss &, 2017. "In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target," Nature, Nature, vol. 547(7664), pages 413-418, July.
    4. Michael Lawrence & Wolfgang Huber & Hervé Pagès & Patrick Aboyoun & Marc Carlson & Robert Gentleman & Martin T Morgan & Vincent J Carey, 2013. "Software for Computing and Annotating Genomic Ranges," PLOS Computational Biology, Public Library of Science, vol. 9(8), pages 1-10, August.
    5. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    6. Jeffrey J. Ishizuka & Robert T. Manguso & Collins K. Cheruiyot & Kevin Bi & Arpit Panda & Arvin Iracheta-Vellve & Brian C. Miller & Peter P. Du & Kathleen B. Yates & Juan Dubrot & Ilana Buchumenski & , 2019. "Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade," Nature, Nature, vol. 565(7737), pages 43-48, January.
    7. Jeffrey T Leek & John D Storey, 2007. "Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable Analysis," PLOS Genetics, Public Library of Science, vol. 3(9), pages 1-12, September.
    8. Claudia Calabrese & Natalie R. Davidson & Deniz Demircioğlu & Nuno A. Fonseca & Yao He & André Kahles & Kjong-Van Lehmann & Fenglin Liu & Yuichi Shiraishi & Cameron M. Soulette & Lara Urban & Liliana , 2020. "Genomic basis for RNA alterations in cancer," Nature, Nature, vol. 578(7793), pages 129-136, February.
    9. Esther Rheinbay & Morten Muhlig Nielsen & Federico Abascal & Jeremiah A. Wala & Ofer Shapira & Grace Tiao & Henrik Hornshøj & Julian M. Hess & Randi Istrup Juul & Ziao Lin & Lars Feuerbach & Radhakris, 2020. "Analyses of non-coding somatic drivers in 2,658 cancer whole genomes," Nature, Nature, vol. 578(7793), pages 102-111, February.
    10. Osnat Bartok & Abhijeet Pataskar & Remco Nagel & Maarja Laos & Eden Goldfarb & Deborah Hayoun & Ronen Levy & Pierre-Rene Körner & Inger Z. M. Kreuger & Julien Champagne & Esther A. Zaal & Onno B. Blei, 2021. "Anti-tumour immunity induces aberrant peptide presentation in melanoma," Nature, Nature, vol. 590(7845), pages 332-337, February.
    11. Shashank J. Patel & Neville E. Sanjana & Rigel J. Kishton & Arash Eidizadeh & Suman K. Vodnala & Maggie Cam & Jared J. Gartner & Li Jia & Seth M. Steinberg & Tori N. Yamamoto & Anand S. Merchant & Gau, 2017. "Identification of essential genes for cancer immunotherapy," Nature, Nature, vol. 548(7669), pages 537-542, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Nina Frey & Luigi Tortola & David Egli & Sharan Janjuha & Tanja Rothgangl & Kim Fabiano Marquart & Franziska Ampenberger & Manfred Kopf & Gerald Schwank, 2022. "Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Dzana Dervovic & Ahmad A. Malik & Edward L. Y. Chen & Masahiro Narimatsu & Nina Adler & Somaieh Afiuni-Zadeh & Dagmar Krenbek & Sebastien Martinez & Ricky Tsai & Jonathan Boucher & Jacob M. Berman & K, 2023. "In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Ting Fu & Kofi Amoah & Tracey W. Chan & Jae Hoon Bahn & Jae-Hyung Lee & Sari Terrazas & Rockie Chong & Sriram Kosuri & Xinshu Xiao, 2024. "Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Gerard Llimos & Vincent Gardeux & Ute Koch & Judith F. Kribelbauer & Antonina Hafner & Daniel Alpern & Joern Pezoldt & Maria Litovchenko & Julie Russeil & Riccardo Dainese & Riccardo Moia & Abdurraouf, 2022. "A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    6. Stefanie Hiltbrunner & Lena Cords & Sabrina Kasser & Sandra N. Freiberger & Susanne Kreutzer & Nora C. Toussaint & Linda Grob & Isabelle Opitz & Michael Messerli & Martin Zoche & Alex Soltermann & Mar, 2023. "Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Irineos Papakyriacou & Ginte Kutkaite & Marta Rúbies Bedós & Divya Nagarajan & Liam P. Alford & Michael P. Menden & Yumeng Mao, 2024. "Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    8. Daniela Klaproth-Andrade & Johannes Hingerl & Yanik Bruns & Nicholas H. Smith & Jakob Träuble & Mathias Wilhelm & Julien Gagneur, 2024. "Deep learning-driven fragment ion series classification enables highly precise and sensitive de novo peptide sequencing," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Yazhong Cui & Yang Miao & Longzhi Cao & Lifang Guo & Yue Cui & Chuanzhe Yan & Zhi Zeng & Mo Xu & Ting Han, 2023. "Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Zhuoran Xu & Quan Li & Luigi Marchionni & Kai Wang, 2023. "PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Sebastian Carrasco Pro & Heather Hook & David Bray & Daniel Berenzy & Devlin Moyer & Meimei Yin & Adam Thomas Labadorf & Ryan Tewhey & Trevor Siggers & Juan Ignacio Fuxman Bass, 2023. "Widespread perturbation of ETS factor binding sites in cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    12. C. W. Ryan & S. L. Regan & E. F. Mills & B. T. McGrath & E. Gong & Y. T. Lai & J. B. Sheingold & K. Patel & T. Horowitz & A. Moccia & Y. C. Tsan & A. Srivastava & S. L. Bielas, 2024. "RING1 missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    13. Ananyo Choudhury & Jean-Tristan Brandenburg & Tinashe Chikowore & Dhriti Sengupta & Palwende Romuald Boua & Nigel J. Crowther & Godfred Agongo & Gershim Asiki & F. Xavier Gómez-Olivé & Isaac Kisiangan, 2022. "Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    14. Julia Joung & Paul C. Kirchgatterer & Ankita Singh & Jang H. Cho & Suchita P. Nety & Rebecca C. Larson & Rhiannon K. Macrae & Rebecca Deasy & Yuen-Yi Tseng & Marcela V. Maus & Feng Zhang, 2022. "CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    15. Tian-Yu Song & Min Long & Hai-Xin Zhao & Miao-Wen Zou & Hong-Jie Fan & Yang Liu & Chen-Lu Geng & Min-Fang Song & Yu-Feng Liu & Jun-Yi Chen & Yu-Lin Yang & Wen-Rong Zhou & Da-Wei Huang & Bo Peng & Zhen, 2021. "Tumor evolution selectively inactivates the core microRNA machinery for immune evasion," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    16. Farnoosh Abbas-Aghababazadeh & Qian Li & Brooke L Fridley, 2018. "Comparison of normalization approaches for gene expression studies completed with high-throughput sequencing," PLOS ONE, Public Library of Science, vol. 13(10), pages 1-21, October.
    17. Dario Zimmerli & Chiara S. Brambillasca & Francien Talens & Jinhyuk Bhin & Renske Linstra & Lou Romanens & Arkajyoti Bhattacharya & Stacey E. P. Joosten & Ana Moises Silva & Nuno Padrao & Max D. Welle, 2022. "MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    18. Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    19. Louise A. Baldwin & Nenad Bartonicek & Jessica Yang & Sunny Z. Wu & Niantao Deng & Daniel L. Roden & Chia-Ling Chan & Ghamdan Al-Eryani & Damien J. Zanker & Belinda S. Parker & Alexander Swarbrick & S, 2022. "DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and immunotherapy response," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. Tara N. Yankee & Sungryong Oh & Emma Wentworth Winchester & Andrea Wilderman & Kelsey Robinson & Tia Gordon & Jill A. Rosenfeld & Jennifer VanOudenhove & Daryl A. Scott & Elizabeth J. Leslie & Justin , 2023. "Integrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48436-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.