IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in metastatic breast cancer

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Claudia Tulotta
  • Diane V. Lefley
  • Charlotte K. Moore
  • Ana E. Amariutei
  • Amy R. Spicer-Hadlington
  • Lewis A. Quayle
  • Russell O. Hughes
  • Khawla Ahmed
  • Victoria Cookson
  • Catherine A. Evans
  • Jayakumar Vadakekolathu
  • Paul Heath
  • Sheila Francis
  • A Graham Pockley
  • Penelope D. Ottewell

Abstract

Breast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast cancer develop disease recurrence in bone and available treatments are only palliative. We have previously shown that production of the pro-inflammatory cytokine interleukin 1B (IL-1B) by breast cancer cells drives bone metastasis in patients and in preclinical in vivo models. In the current study, we have investigated how IL-1B from tumour cells and the microenvironment interact to affect primary tumour growth and bone metastasis through regulation of the immune system and whether targeting IL-1 driven changes to the immune response improves standard of care therapy for breast cancer bone metastasis.
Using syngeneic IL-1B/IL1R1 knock out mouse models in combination with genetic manipulation of tumour cells to overexpress IL-1B/IL1R1, we found that IL-1B signalling elicited an opposite response in primary tumours compared with bone metastases. In primary tumours, IL-1B inhibited growth, by impairing the infiltration of innate immune cell subsets with potential anti-cancer functions but promoted enhanced tumour cell migration and metastasis to bone. In bone, IL-1B stimulated the development of osteolytic metastases and this was accompanied by an increase in neutrophils. In syngeneic models of spontaneous and experimental breast cancer bone metastasis, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited primary tumour growth and metastasis. Anakinra had opposite effects on the immune response compared to standard of care treatment and its anti-inflammatory signature was maintained in the combination therapy. These data suggest that targeting IL-1B signalling may provide a useful therapeutic approach to inhibit bone metastasis and improve efficacy of current treatments for breast cancer patients.

Bibliographical metadata

Original languageEnglish
JournalNPJ Breast Cancer
Publication statusAccepted/In press - 1 Jul 2021