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

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 and OTTEWELL, Penelope D (2021). IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer. npj breast cancer, 7 (1): 95.

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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. 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.

Item Type:	Article
Uncontrolled Keywords:	3202 Clinical sciences; 3211 Oncology and carcinogenesis; 4202 Epidemiology
Identification Number:	https://doi.org/10.1038/s41523-021-00305-w
SWORD Depositor:	Symplectic Elements
Depositing User:	Symplectic Elements
Date Deposited:	04 Jan 2024 15:24
Last Modified:	04 Jan 2024 15:30
URI:	https://shura.shu.ac.uk/id/eprint/32898

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