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.
Highlights
Breast cancer (BC) is the second most common cancer worldwide (2.26 million cases in 2020), accounting for 685,000 deaths
In these microenvironment-derived IL-1B drive the infiltration of immune models, we found that inhibition of IL1R1 did not affect primary cells which may harbour anti-tumour functions in breast primary tumour growth (Fig. 1a, b), whereas inhibition of IL-1B resulted in tumours, in bone, IL-1B supports metastasis formation. increased primary tumour growth (Fig. 1c, d), a b
We found an increase in F4/80+ macrophages in tumours growing in IL-1B−/− mice in the periphery of the tumour compared to the core of the has on breast cancer bone metastasis, E0771 mammary cancer cells were injected into the blood circulation of IL-1Bfl/fl and IL1B−/− mice via intra-cardiac injection
Summary
Breast cancer (BC) is the second most common cancer worldwide (2.26 million cases in 2020), accounting for 685,000 deaths (https://www.who.int/news-room/fact-sheets/detail/cancer, 2020). Breast cancer (BC) is the second most common cancer worldwide (2.26 million cases in 2020), accounting for 685,000 deaths The majority of cancer-related deaths result from tumours spreading to distal sites after which point the disease is currently incurable. Bone is the most common metastatic site in BC—75% of patients with late-stage BC experience recurrence in bone—followed by lung, liver and brain[1,2,3]. The role of the immune system in controlling metastatic tumour cell dormancy in bone remains to be explored[8]. As current treatments for metastatic breast cancer are predominantly palliative, there is an urgent clinical need to identify new biomarkers of metastatic BC and to develop more effective therapies[9]
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