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

Tulotta, C., Lefley, D.V., Moore, C.K., Amariutei, A.E., Spicer-Hadlington, A.R., Quayle, L.A., Hughes, R.O., Ahmed, K., Cookson, V., Evans, C.A., Vadakekolathu, J. ORCID: 0000-0002-2671-4285, Heath, P., Francis, S., Pinteaux, E., Pockley, A.G. ORCID: 0000-0001-9593-6431 and Ottewell, P.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: 95. ISSN 2374-4677

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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: Journal article
Publication Title: npj Breast Cancer
Creators: Tulotta, C., Lefley, D.V., Moore, C.K., Amariutei, A.E., Spicer-Hadlington, A.R., Quayle, L.A., Hughes, R.O., Ahmed, K., Cookson, V., Evans, C.A., Vadakekolathu, J., Heath, P., Francis, S., Pinteaux, E., Pockley, A.G. and Ottewell, P.D.
Publisher: Nature Research
Date: 21 July 2021
Volume: 7
ISSN: 2374-4677
Identifiers:
NumberType
10.1038/s41523-021-00305-wDOI
1454322Other
Rights: © the author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Divisions: Schools > School of Science and Technology
Record created by: Jonathan Gallacher
Date Added: 27 Jul 2021 07:45
Last Modified: 27 Jul 2021 07:45
URI: http://irep.ntu.ac.uk/id/eprint/43640

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