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

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 ca...

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Autores principales:	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, Emmanuel Pinteaux, A. Graham Pockley, Penelope D. Ottewell
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/db7c85c82ea947e69d237a3402f52c96
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spelling	oai:doaj.org-article:db7c85c82ea947e69d237a3402f52c962021-12-02T16:17:53ZIL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer10.1038/s41523-021-00305-w2374-4677https://doaj.org/article/db7c85c82ea947e69d237a3402f52c962021-07-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00305-whttps://doaj.org/toc/2374-4677Abstract 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.Claudia TulottaDiane V. LefleyCharlotte K. MooreAna E. AmariuteiAmy R. Spicer-HadlingtonLewis A. QuayleRussell O. HughesKhawla AhmedVictoria CooksonCatherine A. EvansJayakumar VadakekolathuPaul HeathSheila FrancisEmmanuel PinteauxA. Graham PockleyPenelope D. OttewellNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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 Emmanuel Pinteaux A. Graham Pockley Penelope D. Ottewell IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
description	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.
format	article
author	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 Emmanuel Pinteaux A. Graham Pockley Penelope D. Ottewell
author_facet	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 Emmanuel Pinteaux A. Graham Pockley Penelope D. Ottewell
author_sort	Claudia Tulotta
title	IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
title_short	IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
title_full	IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
title_fullStr	IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
title_full_unstemmed	IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
title_sort	il-1b drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/db7c85c82ea947e69d237a3402f52c96
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IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer

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