颗粒酶B
癌症研究
颗粒酶
免疫系统
免疫疗法
生物标志物
化学
生物
医学
免疫学
T细胞
生物化学
穿孔素
CD8型
作者
Jamie I. Scott,Lorena Mendive‐Tapia,Doireann Gordon,Nicole Barth,Emily Thompson,Zhiming Cheng,David Taggart,Takanori Kitamura,Alberto Bravo-Blas,Ed 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,Margaret C. Frame,Marc Vendrell
标识
DOI:10.1038/s41467-022-29691-w
摘要
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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