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.

乳腺癌骨转移目前无法治愈，约 75% 的晚期乳腺癌患者会出现骨复发，现有的治疗只能起到姑息作用。我们之前已经证明，乳腺癌细胞产生促炎细胞因子白细胞介素-1B (IL-1B) 可驱动患者和临床前体内模型中的骨转移。在当前的研究中，我们研究了肿瘤细胞中的 IL-1B 与微环境如何相互作用，通过免疫系统的调节影响原发性肿瘤生长和骨转移，以及靶向 IL-1 驱动的免疫反应变化是否可以提高护理标准乳腺癌骨转移的治疗。使用同基因 IL-1B/IL1R1 敲除小鼠模型结合肿瘤细胞的基因操作以过度表达 IL-1B/IL1R1，我们发现与骨转移相比，IL-1B 信号在原发性肿瘤中引起相反的反应。在原发性肿瘤中，IL-1B 通过损害具有潜在抗癌功能的先天免疫细胞亚群的浸润来抑制生长，但促进肿瘤细胞迁移增强。在骨骼中，IL-1B 刺激溶骨性转移的发生。在乳腺癌同基因模型中，将标准护理治疗（阿霉素和唑来膦酸）与 IL-1 受体拮抗剂阿那白滞素相结合，可抑制原发肿瘤的生长和转移。与标准护理治疗相比，阿那白滞素对免疫反应具有相反的作用，并且在联合治疗中保留了其抗炎特征。这些数据表明，靶向 IL-1B 信号传导可能提供一种有用的治疗方法来抑制骨转移并提高乳腺癌患者当前治疗的疗效。