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

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 i...

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Veröffentlicht in:Nature communications Jg. 13; H. 1; S. 2366 - 11
Hauptverfasser: Scott, Jamie I., Mendive-Tapia, Lorena, Gordon, Doireann, Barth, Nicole D., Thompson, Emily J., Cheng, Zhiming, Taggart, David, Kitamura, Takanori, Bravo-Blas, Alberto, Roberts, Edward W., Juarez-Jimenez, Jordi, Michel, Julien, Piet, Berber, de Vries, I. Jolanda, Verdoes, Martijn, Dawson, John, Carragher, Neil O., Connor, Richard A. O’, Akram, Ahsan R., Frame, Margaret, Serrels, Alan, Vendrell, Marc
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 02.05.2022
Nature Publishing Group
Nature Portfolio
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AKT protein
Animals
Anticancer properties
Antitumor activity
Biomarkers
Biopsy
Cancer
Cell activation
Chemical synthesis
Enzyme inhibitors
Fluorescence resonance energy transfer
Fluorescent indicators
Granzyme B
Granzymes
Humanities and Social Sciences
Humans
Immune system
Immunotherapy
Kinases
Lung cancer
Lung Neoplasms - drug therapy
Lymphocytes
Lymphocytes T
Mice
Molecular dynamics
multidisciplinary
Peptides
Science
Science (multidisciplinary)
Tumors
ISSN:2041-1723, 2041-1723
Online-Zugang:Volltext
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Zusammenfassung: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. Granzyme B is found in activated T cells and can be used as a marker of T cell activation. Here, the authors generate a fluorescent probe that can detect Granzyme B levels in tumours, and has the potential to be used as a biomarker of response to immunotherapy.
Bibliographie:ObjectType-Article-1
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-29691-w