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

• Published in: NPJ breast cancer Vol. 7; no. 1; p. 95
• Main Authors: Tulotta, Claudia, Lefley, Diane V., Moore, Charlotte K., Amariutei, Ana E., Spicer-Hadlington, Amy R., Quayle, Lewis A., Hughes, Russell O., Ahmed, Khawla, Cookson, Victoria, Evans, Catherine A., Vadakekolathu, Jayakumar, Heath, Paul, Francis, Sheila, Pinteaux, Emmanuel, Pockley, A. Graham, Ottewell, Penelope D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-07-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1347; 692/4028/67/580; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cancer therapies; Cell Biology; Human Genetics; Metastasis; Oncology; Tumors
• ISSN: 2374-4677; 2374-4677
• DOI: 10.1038/s41523-021-00305-w

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. In bone, IL-1B stimulated the development of osteolytic metastases. In syngeneic models of breast cancer, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited both 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.