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
Rok vydání: 2022
Předmět:
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