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

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 IFN beta is targeted, not IFN alpha. We identify Ly6C(+)/CD11b(+) inflammatory monocytes as the primary source of IFN beta 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 IFN beta signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response. Immune checkpoint blockade (ICB) is partially successful as a cancer therapy. Here using mouse models, the authors transcriptionally monitor responding and non-responding tumours showing that responding tumours were associated with transient IFN-beta signalling which could promote the anti-tumour response.

Automated summary

The biological determinants of the response to immune checkpoint blockade (ICB) in cancer are not fully understood. This study shows that responding tumors are associated with transient IFN-beta signaling, which can promote the anti-tumor response. The authors also identify inflammatory monocytes as the primary source of IFN beta and find that active type-I-IFN signaling in tumor-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB.