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A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies

Author

Listed:
  • Jamie I. Scott

    (The University of Edinburgh)

  • Lorena Mendive-Tapia

    (The University of Edinburgh)

  • Doireann Gordon

    (The University of Edinburgh)

  • Nicole D. Barth

    (The University of Edinburgh)

  • Emily J. Thompson

    (The University of Edinburgh)

  • Zhiming Cheng

    (The University of Edinburgh)

  • David Taggart

    (The University of Edinburgh)

  • Takanori Kitamura

    (The University of Edinburgh)

  • Alberto Bravo-Blas

    (Cancer Research UK Beatson Institute)

  • Edward W. Roberts

    (Cancer Research UK Beatson Institute)

  • Jordi Juarez-Jimenez

    (The University of Edinburgh)

  • Julien Michel

    (The University of Edinburgh)

  • Berber Piet

    (Radboud University Medical Centre)

  • I. Jolanda Vries

    (Radboud University Medical Centre)

  • Martijn Verdoes

    (Radboud University Medical Centre)

  • John Dawson

    (The University of Edinburgh)

  • Neil O. Carragher

    (The University of Edinburgh)

  • Richard A. O’ Connor

    (The University of Edinburgh)

  • Ahsan R. Akram

    (The University of Edinburgh)

  • Margaret Frame

    (The University of Edinburgh)

  • Alan Serrels

    (The University of Edinburgh)

  • Marc Vendrell

    (The University of Edinburgh)

Abstract

Immunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probe H5 with an optimal fit into granzyme B. We demonstrate that probe H5 enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probe H5 may enable the monitoring of early responses to anticancer treatments using tissue biopsies.

Suggested Citation

  • Jamie I. Scott & Lorena Mendive-Tapia & Doireann Gordon & Nicole D. Barth & Emily J. Thompson & Zhiming Cheng & David Taggart & Takanori Kitamura & Alberto Bravo-Blas & Edward W. Roberts & Jordi Juare, 2022. "A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29691-w
    DOI: 10.1038/s41467-022-29691-w
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