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Protease dysregulation during response and resistance to immune checkpoint blockade therapy (RNA-seq)

ABSTRACT: Immune checkpoint blockade (ICB) therapy does not benefit the majority of treated patients, and those who respond to the therapy can become resistant to it. Here we report the design and performance of systemically administered activity sensors conjugated to anti-programmed cell death protein 1 (αPD1) antibodies for the monitoring of antitumour responses to ICB therapy. RNA sequencing analysis revealed that differential expression of tumour and immune proteases underpins ICB response and resistance. We then designed a library of mass-barcoded sensors that, when cleaved by proteases, are released into urine, where they can be detected by mass spectrometry. By using syngeneic mouse models of colorectal cancer, we show that random-forest classification trained on mass-spectrometry signatures can be used to detect early antitumour responses and to discriminate resistance to ICB therapy driven by loss-of-function mutations in either the B2m or Jak1 genes. Our data supports the use of activity-based biomarkers that leverage protease dysregulation for response assessment and classification of refractory tumours.

ORGANISM(S): Mus musculus

PROVIDER: GSE192796 | GEO | 2022/02/15

REPOSITORIES: GEO

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