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

Author

Listed:
  • Rachael M. Zemek

    (National Centre for Asbestos Related Diseases
    University of Western Australia
    University of Western Australia)

  • Wee Loong Chin

    (University of Western Australia
    Sir Charles Gairdner Hospital
    University of Western Australia)

  • Vanessa S. Fear

    (National Centre for Asbestos Related Diseases
    University of Western Australia
    University of Western Australia)

  • Ben Wylie

    (University of Western Australia)

  • Thomas H. Casey

    (National Centre for Asbestos Related Diseases
    University of Western Australia)

  • Cath Forbes

    (National Centre for Asbestos Related Diseases
    University of Western Australia
    University of Western Australia)

  • Caitlin M. Tilsed

    (National Centre for Asbestos Related Diseases
    University of Western Australia)

  • Louis Boon

    (Polpharma Biologics, Yalelaan 46, Alexander Numan Building)

  • Belinda B. Guo

    (The University of Western Australia, Nedlands)

  • Anthony Bosco

    (University of Western Australia)

  • Alistair R. R. Forrest

    (The University of Western Australia, Nedlands)

  • Michael J. Millward

    (Sir Charles Gairdner Hospital
    University of Western Australia)

  • Anna K. Nowak

    (National Centre for Asbestos Related Diseases
    Sir Charles Gairdner Hospital
    University of Western Australia)

  • Richard A. Lake

    (National Centre for Asbestos Related Diseases
    University of Western Australia)

  • Timo Lassmann

    (University of Western Australia)

  • W. Joost Lesterhuis

    (National Centre for Asbestos Related Diseases
    University of Western Australia
    University of Western Australia)

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.

Suggested Citation

  • Rachael M. Zemek & Wee Loong Chin & Vanessa S. Fear & Ben Wylie & Thomas H. Casey & Cath Forbes & Caitlin M. Tilsed & Louis Boon & Belinda B. Guo & Anthony Bosco & Alistair R. R. Forrest & Michael J. , 2022. "Temporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32567-8
    DOI: 10.1038/s41467-022-32567-8
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