@article{6833f937edfa4535b4a009f765cf452a,
title = "A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies",
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.",
author = "Jamie Scott and {Mendive Tapia}, Lorena and Doireann Gordon and Nicole Barth and Emily Thompson and Zhiming Cheng and David Taggart and Takanori Kitamura and Blas, {Alberto B} and Roberts, {Edward W} and {Juarez Jimenez}, Jordi and Julien Michel and Berber Piet and {de Vries}, {I Jolanda} and Martijn Verdoes and Dawson, {John C} and Carragher, {Neil O} and O'Connor, {Richard A} and Akram, {Ahsan R} and Alan Serrels and Frame, {Margaret C} and Marc Vendrell",
note = "Funding Information: J.I.S. and N.D.B. acknowledge funding from OPTIMA (EP/L016559/1). J.I.S. acknowledges funding from the Scottish Funding Council (H14052). L.M.T. acknowledges the support of Fundacion Antonio Martin Escudero (FAME) in the form of a post-doctoral fellowship. D.G. acknowledges funding from the Medical Research Council (MR/R01566X/1). T.K. acknowledges funding from an MRC Career Development Award (MR/S006982/1) and an MRC Centre Grant (MR/N022556/1). E.W.R. acknowledges funding from the Beatson Institute (A31287). J.J.J. and J.M. acknowledge funding from the Engineering and Physical Sciences Research Council (EP/P011330/1). N.O.C. acknowledges funding from Cancer Research UK (C42454/A28596) and the Brain Tumour Charity (GN-000676). A.R.A. acknowledges funding from a Cancer Research UK Clinician Scientist award (A24867). M.V. acknowledges funding from an ERC Consolidator Grant (DYNAFLUORS, 771443) and an ERC Proof of Concept Grant (957535). This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement (859908). We thank the technical support from Tom G van Oorschot at the Radboud University Medical Centre, the QMRI Flow Cytometry and Confocal Advanced Light Microscopy facilities at the University of Edinburgh and Luxembourg Bio Technologies Ltd. (Rehovot) for the kind supply of reagents for peptide synthesis. We acknowledge biorender.com for assistance with figure creation. Funding Information: J.I.S. and N.D.B. acknowledge funding from OPTIMA (EP/L016559/1). J.I.S. acknowledges funding from the Scottish Funding Council (H14052). L.M.T. acknowledges the support of Fundacion Antonio Martin Escudero (FAME) in the form of a post-doctoral fellowship. D.G. acknowledges funding from the Medical Research Council (MR/R01566X/1). T.K. acknowledges funding from an MRC Career Development Award (MR/S006982/1) and an MRC Centre Grant (MR/N022556/1). E.W.R. acknowledges funding from the Beatson Institute (A31287). J.J.J. and J.M. acknowledge funding from the Engineering and Physical Sciences Research Council (EP/P011330/1). N.O.C. acknowledges funding from Cancer Research UK (C42454/A28596) and the Brain Tumour Charity (GN-000676). A.R.A. acknowledges funding from a Cancer Research UK Clinician Scientist award (A24867). M.V. acknowledges funding from an ERC Consolidator Grant (DYNAFLUORS, 771443) and an ERC Proof of Concept Grant (957535). This project has received funding from the European Union?s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement (859908). We thank the technical support from Tom G van Oorschot at the Radboud University Medical Centre, the QMRI Flow Cytometry and Confocal Advanced Light Microscopy facilities at the University of Edinburgh and Luxembourg Bio Technologies Ltd. (Rehovot) for the kind supply of reagents for peptide synthesis. We acknowledge biorender.com for assistance with figure creation. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = may,
day = "2",
doi = "10.1038/s41467-022-29691-w",
language = "English",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}