Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29691-w
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Funding
- OPTIMA [EP/L016559/1]
- Scottish Funding Council [H14052]
- Fundacion Antonio Martin Escudero (FAME)
- Medical Research Council [MR/R01566X/1]
- MRC Career Development Award [MR/S006982/1]
- MRC Centre Grant [MR/N022556/1]
- Beatson Institute [A31287]
- Engineering and Physical Sciences Research Council [EP/P011330/1]
- Cancer Research UK [C42454/A28596]
- Brain Tumour Charity [GN-000676]
- Cancer Research UK Clinician Scientist award [A24867]
- ERC Consolidator Grant (DYNAFLUORS) [771443]
- ERC Proof of Concept Grant [957535]
- European Union [859908]
- MRC [MR/S006982/1] Funding Source: UKRI
- European Research Council (ERC) [957535, 771443] Funding Source: European Research Council (ERC)
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This study presents a rational design of a fluorogenic peptide that can detect active granzyme B as a biomarker of immune-mediated anticancer action. The probe enables real-time detection of T cell-mediated anticancer activity and has the potential to be used as a biomarker for early response to anticancer treatments.
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. Granzyme B is found in activated T cells and can be used as a marker of T cell activation. Here, the authors generate a fluorescent probe that can detect Granzyme B levels in tumours, and has the potential to be used as a biomarker of response to immunotherapy.
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