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...

ver descrição completa

Detalhes bibliográficos
Autores: 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., Juárez Jiménez, Jordi, Michel, Julien, Piet, Berber, Vries, I. Jolanda de, Verdoes, Martijn, Dawson, John, Carragher, Neil, O' Connor, Richard A., Akram, Ahsan R., Frame, Margaret, Serrels, Alan, Vendrell, Marc
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/189387
Acesso em linha:https://hdl.handle.net/2445/189387
Access Level:acceso abierto
Palavra-chave:Càncer
Pèptids
Síntesi orgànica
Cancer
Peptides
Organic synthesis
Descrição
Resumo: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.

Registos relacionados