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; W Joost Lesterhuis

doi:10.1038/s41467-022-32567-8

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

Nat Commun. 2022 Aug 19;13(1):4895. doi: 10.1038/s41467-022-32567-8.

Authors

Rachael M Zemek^#^{1

2

3}, Wee Loong Chin^#^{3

4

5}, Vanessa S Fear^{1

2

3}, Ben Wylie³, Thomas H Casey^{1

2}, Cath Forbes^{1

2

3}, Caitlin M Tilsed^{1

2}, Louis Boon⁶, Belinda B Guo⁷, Anthony Bosco³, Alistair R R Forrest⁷, Michael J Millward^{4

5}, Anna K Nowak^{1

4

5}, Richard A Lake^{1

2}, Timo Lassmann⁸, W Joost Lesterhuis^{9

10

11}

Affiliations

¹ National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia.
² School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia.
³ Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia.
⁴ Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
⁵ School of Medicine, University of Western Australia, Crawley, WA, 6009, Australia.
⁶ Polpharma Biologics, Yalelaan 46, Alexander Numan Building, 3584 CM, Utrecht, The Netherlands.
⁷ Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Perth, WA, 6009, Australia.
⁸ Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia. [email protected].
⁹ National Centre for Asbestos Related Diseases, Nedlands, WA, 6009, Australia. [email protected].
¹⁰ School of Biomedical Sciences, University of Western Australia, Crawley, WA, 6009, Australia. [email protected].
¹¹ Telethon Kids Institute, University of Western Australia, Nedlands, WA, 6009, Australia. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Interferon Type I*
Interferon-alpha
Interferon-beta / genetics
Interferon-beta / therapeutic use
Mice
Neoplasms* / drug therapy
Neoplasms* / genetics
Signal Transduction

Substances

Interferon Type I
Interferon-alpha
Interferon-beta