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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 2366 (05 02 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35501326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Peptides
• Granzymes

Topics

• Animals
• Biopsy
• Granzymes
• Humans
• Immunotherapy
• Lung Neoplasms (drug therapy)
• Mice
• Peptides
• Research