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

Autor: Zemek RM; National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia.; School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia.; Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia., Chin WL; Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia.; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.; School of Medicine, University of Western Australia, Crawley, WA, 6009, Australia., Fear VS; National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia.; School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia.; Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia., Wylie B; Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia., Casey TH; National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia.; School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia., Forbes C; National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia.; School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia.; Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia., Tilsed CM; National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia.; School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia., Boon L; Polpharma Biologics, Yalelaan 46, Alexander Numan Building, 3584 CM, Utrecht, The Netherlands., Guo BB; Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, WA, 6009, Australia., Bosco A; Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia., Forrest ARR; Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, WA, 6009, Australia., Millward MJ; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.; School of Medicine, University of Western Australia, Crawley, WA, 6009, Australia., Nowak AK; National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia.; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.; School of Medicine, University of Western Australia, Crawley, WA, 6009, Australia., Lake RA; National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia.; School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia., Lassmann T; Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia. timo.lassmann@telethonkids.org.au., Lesterhuis WJ; National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia. willem.lesterhuis@uwa.edu.au.; School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia. willem.lesterhuis@uwa.edu.au.; Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia. willem.lesterhuis@uwa.edu.au.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Aug 19; Vol. 13 (1), pp. 4895. Date of Electronic Publication: 2022 Aug 19.
DOI: 10.1038/s41467-022-32567-8
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: