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Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA

Author

Listed:
  • K. G. Paulson

    (University of Washington
    Fred Hutchinson Cancer Research Center
    Seattle Cancer Care Alliance)

  • V. Voillet

    (Fred Hutchinson Cancer Research Center)

  • M. S. McAfee

    (Fred Hutchinson Cancer Research Center)

  • D. S. Hunter

    (Fred Hutchinson Cancer Research Center)

  • F. D. Wagener

    (Fred Hutchinson Cancer Research Center)

  • M. Perdicchio

    (Fred Hutchinson Cancer Research Center
    Roche)

  • W. J. Valente

    (Fred Hutchinson Cancer Research Center)

  • S. J. Koelle

    (University of Washington
    Fred Hutchinson Cancer Research Center)

  • C. D. Church

    (University of Washington)

  • N. Vandeven

    (University of Washington)

  • H. Thomas

    (University of Washington)

  • A. G. Colunga

    (University of Washington)

  • J. G. Iyer

    (University of Washington)

  • C. Yee

    (MD Anderson Cancer Center)

  • R. Kulikauskas

    (University of Washington)

  • D. M. Koelle

    (University of Washington
    Fred Hutchinson Cancer Research Center
    Benaroya Research Institute)

  • R. H. Pierce

    (Fred Hutchinson Cancer Research Center)

  • J. H. Bielas

    (University of Washington
    Fred Hutchinson Cancer Research Center)

  • P. D. Greenberg

    (University of Washington
    Fred Hutchinson Cancer Research Center)

  • S. Bhatia

    (University of Washington
    Fred Hutchinson Cancer Research Center
    Seattle Cancer Care Alliance)

  • R. Gottardo

    (University of Washington
    Fred Hutchinson Cancer Research Center)

  • P. Nghiem

    (University of Washington
    Fred Hutchinson Cancer Research Center
    Seattle Cancer Care Alliance)

  • A. G. Chapuis

    (University of Washington
    Fred Hutchinson Cancer Research Center
    Seattle Cancer Care Alliance)

Abstract

Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor–immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.

Suggested Citation

  • K. G. Paulson & V. Voillet & M. S. McAfee & D. S. Hunter & F. D. Wagener & M. Perdicchio & W. J. Valente & S. J. Koelle & C. D. Church & N. Vandeven & H. Thomas & A. G. Colunga & J. G. Iyer & C. Yee &, 2018. "Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06300-3
    DOI: 10.1038/s41467-018-06300-3
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    Cited by:

    1. 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.
    2. Kuang Du & Shiyou Wei & Zhi Wei & Dennie T. Frederick & Benchun Miao & Tabea Moll & Tian Tian & Eric Sugarman & Dmitry I. Gabrilovich & Ryan J. Sullivan & Lunxu Liu & Keith T. Flaherty & Genevieve M. , 2021. "Pathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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