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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
Nature communications, 05/2022, Letnik: 13, Številka: 1Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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