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Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Author

Listed:
  • Moshe Sade-Feldman

    (Massachusetts General Hospital Cancer Center
    Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

  • Yunxin J. Jiao

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
    Harvard Medical School)

  • Jonathan H. Chen

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
    Massachusetts General Hospital)

  • Michael S. Rooney

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

  • Michal Barzily-Rokni

    (Massachusetts General Hospital Cancer Center)

  • Jean-Pierre Eliane

    (Massachusetts General Hospital)

  • Stacey L. Bjorgaard

    (Massachusetts General Hospital Cancer Center
    Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

  • Marc R. Hammond

    (Massachusetts General Hospital Cancer Center)

  • Hans Vitzthum

    (Massachusetts General Hospital Cancer Center)

  • Shauna M. Blackmon

    (Massachusetts General Hospital Cancer Center)

  • Dennie T. Frederick

    (Massachusetts General Hospital Cancer Center)

  • Mehlika Hazar-Rethinam

    (Massachusetts General Hospital Cancer Center)

  • Brandon A. Nadres

    (Massachusetts General Hospital Cancer Center)

  • Emily E. Seventer

    (Massachusetts General Hospital Cancer Center)

  • Sachet A. Shukla

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
    Dana-Farber Cancer Institute)

  • Keren Yizhak

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

  • John P. Ray

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

  • Daniel Rosebrock

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

  • Dimitri Livitz

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

  • Viktor Adalsteinsson

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

  • Gad Getz

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
    Massachusetts General Hospital)

  • Lyn M. Duncan

    (Massachusetts General Hospital)

  • Bo Li

    (Dana-Farber Cancer Institute)

  • Ryan B. Corcoran

    (Massachusetts General Hospital Cancer Center)

  • Donald P. Lawrence

    (Massachusetts General Hospital Cancer Center)

  • Anat Stemmer-Rachamimov

    (Massachusetts General Hospital)

  • Genevieve M. Boland

    (Massachusetts General Hospital)

  • Dan A. Landau

    (Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
    New York Genome Center, NYC
    Weill Cornell Medicine, NYC)

  • Keith T. Flaherty

    (Massachusetts General Hospital Cancer Center)

  • Ryan J. Sullivan

    (Massachusetts General Hospital Cancer Center)

  • Nir Hacohen

    (Massachusetts General Hospital Cancer Center
    Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard)

Abstract

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

Suggested Citation

  • Moshe Sade-Feldman & Yunxin J. Jiao & Jonathan H. Chen & Michael S. Rooney & Michal Barzily-Rokni & Jean-Pierre Eliane & Stacey L. Bjorgaard & Marc R. Hammond & Hans Vitzthum & Shauna M. Blackmon & De, 2017. "Resistance to checkpoint blockade therapy through inactivation of antigen presentation," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01062-w
    DOI: 10.1038/s41467-017-01062-w
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    Cited by:

    1. Meghana Pagadala & Timothy J. Sears & Victoria H. Wu & Eva Pérez-Guijarro & Hyo Kim & Andrea Castro & James V. Talwar & Cristian Gonzalez-Colin & Steven Cao & Benjamin J. Schmiedel & Shervin Goudarzi , 2023. "Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Kelsy C. Cotto & Yang-Yang Feng & Avinash Ramu & Megan Richters & Sharon L. Freshour & Zachary L. Skidmore & Huiming Xia & Joshua F. McMichael & Jason Kunisaki & Katie M. Campbell & Timothy Hung-Po Ch, 2023. "Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. 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.
    4. Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Su Yin Lim & Elena Shklovskaya & Jenny H. Lee & Bernadette Pedersen & Ashleigh Stewart & Zizhen Ming & Mal Irvine & Brindha Shivalingam & Robyn P. M. Saw & Alexander M. Menzies & Matteo S. Carlino & R, 2023. "The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Brian D. Lehmann & Antonio Colaprico & Tiago C. Silva & Jianjiao Chen & Hanbing An & Yuguang Ban & Hanchen Huang & Lily Wang & Jamaal L. James & Justin M. Balko & Paula I. Gonzalez-Ericsson & Melinda , 2021. "Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    7. Ariane F. Busso-Lopes & Leandro X. Neves & Guilherme A. Câmara & Daniela C. Granato & Marco Antônio M. Pretti & Henry Heberle & Fábio M. S. Patroni & Jamile Sá & Sami Yokoo & César Rivera & Romênia R., 2022. "Connecting multiple microenvironment proteomes uncovers the biology in head and neck cancer," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    8. 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.
    9. Xiulan Lai & Wenrui Hao & Avner Friedman, 2020. "TNF-α inhibitor reduces drug-resistance to anti-PD-1: A mathematical model," PLOS ONE, Public Library of Science, vol. 15(4), pages 1-21, April.
    10. Miles C. Andrews & Junna Oba & Chang-Jiun Wu & Haifeng Zhu & Tatiana Karpinets & Caitlin A. Creasy & Marie-Andrée Forget & Xiaoxing Yu & Xingzhi Song & Xizeng Mao & A. Gordon Robertson & Gabriele Roma, 2022. "Multi-modal molecular programs regulate melanoma cell state," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    11. Denise Lau & Sonal Khare & Michelle M. Stein & Prerna Jain & Yinjie Gao & Aicha BenTaieb & Tim A. Rand & Ameen A. Salahudeen & Aly A. Khan, 2022. "Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    12. 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.
    13. Laura Y. Zhou & Fei Zou & Wei Sun, 2023. "Prioritizing candidate peptides for cancer vaccines through predicting peptide presentation by HLA‐I proteins," Biometrics, The International Biometric Society, vol. 79(3), pages 2664-2676, September.

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