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

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 Juarez-Jimenez, Julien Michel, Berber Piet, I. Jolanda Vries, Martijn Verdoes, John Dawson, Neil O. Carragher, Richard A. O’ Connor, Ahsan R. Akram, Margaret Frame, Alan Serrels and Marc Vendrell ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29691-w

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