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

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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 probeH5with an optimal fit into granzyme B. We demonstrate that probeH5enables 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 probeH5may enable the monitoring of early responses to anticancer treatments using tissue biopsies.
Funding Information
  • Scottish Funding Council (H14052)
  • RCUK | Medical Research Council (MR/R01566X/1, MR/S006982/1, MR/N022556/1)
  • RCUK | Engineering and Physical Sciences Research Council (EP/P011330/1)
  • Cancer Research UK (C42454/A28596, A24867)
  • Brain Tumour Charity (GN-000676)
  • European Commission (771443, 957535, 859908)

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