Temporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice

Rachael Zemek, Melvin Chin, Vanessa Fear, Ben Wylie, Tom Casey, Catherine Forbes, Caitlin Tilsed, Louis Boon, Belinda Guo, Anthony Bosco, Alistair Forrest, Michael Millward, Anna Nowak, Richard Lake, Timo Lassmann, Willem Lesterhuis

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C+/CD11b+ inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
Original languageEnglish
Article number4895
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022

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