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

2022; Nature Portfolio; Volume: 13; Issue: 1 Linguagem: Inglês

10.1038/s41467-022-29691-w

2041-1723

Jamie I. Scott, Lorena Mendive‐Tapia, Doireann Gordon, Nicole D. Barth, Emily Thompson, Zhiming Cheng, David Taggart, Takanori Kitamura, Alberto Bravo‐Blas, Edward W. Roberts, Jordi Juárez‐Jiménez, Julien Michel, Berber Piet, I. Jolanda M. de Vries, Martijn Verdoes, John C. Dawson, Neil O. Carragher, Richard A. Connor, Ahsan R. Akram, Margaret C. Frame, Alan Serrels, Marc Vendrell,

Immune Cell Function and Interaction

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.