A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies
| Autor: | 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 de Vries, Martijn Verdoes, John Dawson, Neil O. Carragher, Richard A. O’ Connor, Ahsan R. Akram, Margaret Frame, Alan Serrels, Marc Vendrell |
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| Rok vydání: | 2022 |
| Předmět: |
Síntesi orgànica
Lung Neoplasms Multidisciplinary Biopsy Research Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] General Physics and Astronomy Organic synthesis General Chemistry Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] Granzymes General Biochemistry Genetics and Molecular Biology Mice All institutes and research themes of the Radboud University Medical Center Animals Humans Immunotherapy Pèptids Càncer Peptides Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] Cancer |
| Zdroj: | Nature Communications, 13, 1 Dipòsit Digital de la UB Universidad de Barcelona Scott, J, Mendive Tapia, L, Gordon, D, Barth, N, Thompson, E, Cheng, Z, Taggart, D, Kitamura, T, Blas, A B, Roberts, E W, Juarez Jimenez, J, Michel, J, Piet, B, de Vries, I J, Verdoes, M, Dawson, J C, Carragher, N O, O'Connor, R A, Akram, A R, Serrels, A, Frame, M C & Vendrell, M 2022, ' A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies ', Nature Communications . https://doi.org/10.1038/s41467-022-29691-w Nature Communications, 13 Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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 probeH5with an optimal fit into granzyme B. We demonstrate that probeH5enables 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 probeH5may enable the monitoring of early responses to anticancer treatments using tissue biopsies. |
| Databáze: | OpenAIRE |
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