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Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

Author

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  • Lauren E. Stopfer

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Joshua M. Mesfin

    (Massachusetts Institute of Technology)

  • Brian A. Joughin

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Douglas A. Lauffenburger

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Forest M. White

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

Peptides bound to class I major histocompatibility complexes (MHC) play a critical role in immune cell recognition and can trigger an antitumor immune response in cancer. Surface MHC levels can be modulated by anticancer agents, altering immunity. However, understanding the peptide repertoire’s response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking normalization controls. We describe an experimental platform that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging to quantify peptide repertoire alterations using low sample input. HipMHCs improve quantitative accuracy of peptide repertoire changes by normalizing for variation across analyses and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens, which can inform immunotherapy design. Applying this platform in melanoma cell lines to profile the immunopeptidome response to CDK4/6 inhibition and interferon-γ — known modulators of antigen presentation — uncovers treatment-specific alterations, connecting the intracellular response to extracellular immune presentation.

Suggested Citation

  • Lauren E. Stopfer & Joshua M. Mesfin & Brian A. Joughin & Douglas A. Lauffenburger & Forest M. White, 2020. "Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16588-9
    DOI: 10.1038/s41467-020-16588-9
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    Cited by:

    1. Melih Yilmaz & William E. Fondrie & Wout Bittremieux & Carlo F. Melendez & Rowan Nelson & Varun Ananth & Sewoong Oh & William Stafford Noble, 2024. "Sequence-to-sequence translation from mass spectra to peptides with a transformer model," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Huapan Fang & Zhaopei Guo & Jie Chen & Lin Lin & Yingying Hu & Yanhui Li & Huayu Tian & Xuesi Chen, 2021. "Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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