New Investigator Symposium Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Temporally restricted activation of IFNβ signaling from inflammatory monocytes determines response to immune checkpoint therapy (#67)

Rachael M Zemek 1 2 3 , Wee Loong Chin 1 3 4 , Vanessa S Fear 1 2 3 , Thomas H Casey 1 3 , Ben Wylie 2 , Cath Forbes 1 2 3 , Caitlin Tilsed 1 3 , Belinda B Guo 5 , Anthony Bosco 2 , Alistair RR Forrest 5 , Michael J Millward 1 4 , Anna K Nowak 1 3 4 , Richard A Lake 1 3 , Timo Lassmann 2 , W. Joost Lesterhuis 1 2 3
  1. University of Western Australia, Perth, WA, Australia
  2. Telethon Kids Institute, Nedlands, WA, Australia
  3. National Centre for Asbestos Related Diseases, Nedlands, WA, Australia
  4. Department of Medical Oncology, Sir Chales Gairdner Hospital, Perth, WA, Australia
  5. Harry Perkins Insitute of Medical Research, Perth, WA, Australia

Introduction: Immune checkpoint blockade (ICB) uses antibodies to block inhibitory receptors, allowing immune cells to attack and kill cancer cells. This therapy has resulted in complete regression of tumours in some patients, but no response in others. The biological determinants of the response to ICB in cancer remain incompletely understood. Little is known about dynamic biological events that under-pin therapeutic efficacy due to the inability to frequently sample tumours in patients.

Procedures: We developed bilateral tumour mouse models where ICB either leads to a response or a failure to respond in both tumours, allowing us to take one tumour during ICB therapy while determining the response from the remaining tumour. We mapped the gene expression of 144 responding and non-responding tumours from two mouse models at four time-points during ICB using bulk and single-cell RNAseq.

Results: We found that responding tumours displayed a dynamic on/off pattern of type I interferon (IFN) signaling, while in non-responsive tumours IFN was slowly and persistently activated. By mimicking the on/off IFN signal using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies we markedly improved ICB efficacy, but only when IFNβ or its receptor was targeted, not IFNα. We identified Ly6C+/CD11b+ inflammatory monocytes as the primary source of IFNβ and found that active type I IFN signaling in tumour-infiltrating inflammatory monocytes was associated with T cell expansion in patients treated with ICB.

Conclusions: Our results suggest that on/off activation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response. This is the first example that time-dependent modulation of a drug target is required to achieve a more favorable anti-cancer effect.