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

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. Millward, Anna K. Nowak, Richard A. Lake, Timo Lassmann () and W. Joost Lesterhuis ()
Additional contact information
Rachael M. Zemek: National Centre for Asbestos Related Diseases
Wee Loong Chin: University of Western Australia
Vanessa S. Fear: National Centre for Asbestos Related Diseases
Ben Wylie: University of Western Australia
Thomas H. Casey: National Centre for Asbestos Related Diseases
Cath Forbes: National Centre for Asbestos Related Diseases
Caitlin M. Tilsed: National Centre for Asbestos Related Diseases
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
Anna K. Nowak: National Centre for Asbestos Related Diseases
Richard A. Lake: National Centre for Asbestos Related Diseases
Timo Lassmann: University of Western Australia
W. Joost Lesterhuis: National Centre for Asbestos Related Diseases

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-32567-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32567-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-32567-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().