IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer.
IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer.
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DOI：
10.1038/s41523-021-00305-w
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发表时间：
2021-07-21
影响因子：
5.9
通讯作者：
Ottewell PD
中科院分区：
文献类型：
--
作者：
Tulotta C;Lefley DV;Moore CK;Amariutei AE;Spicer-Hadlington AR;Quayle LA;Hughes RO;Ahmed K;Cookson V;Evans CA;Vadakekolathu J;Heath P;Francis S;Pinteaux E;Pockley AG;Ottewell PD
乳腺癌骨转移目前是不可治愈的，约75%的晚期乳腺癌患者会出现骨复发，可用的治疗方法仅是姑息性的。我们先前已经表明，乳腺癌细胞产生的促炎细胞因子白细胞介素-1B（IL-1B）驱动患者和临床前体内模型的骨转移。在目前的研究中，我们研究了来自肿瘤细胞的IL-1B和微环境如何相互作用，通过调节免疫系统来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改善了乳腺癌骨转移的标准治疗。使用同基因IL-1B/IL 1 R1敲除小鼠模型结合肿瘤细胞的遗传操作以过表达IL-1B/IL 1 R1，我们发现与骨转移相比，IL-1B信号传导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，但促进增强的肿瘤细胞迁移。在骨中，IL-1B刺激溶骨性转移的发展。在同基因乳腺癌模型中，联合标准治疗（多柔比星和唑来膦酸）与IL-1受体拮抗剂阿那白滞素抑制原发性肿瘤生长和转移。与标准治疗相比，阿那白滞素对免疫应答具有相反的作用，并且其抗炎特征在联合治疗中得以维持。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，以抑制骨转移，提高乳腺癌患者目前治疗的疗效。
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.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
4.6
作者：
Guo B;Fu S;Zhang J;Liu B;Li Z
通讯作者：
Li Z
影响因子：
7.2
作者：
Kersten K;Coffelt SB;Hoogstraat M;Verstegen NJM;Vrijland K;Ciampricotti M;Doornebal CW;Hau CS;Wellenstein MD;Salvagno C;Doshi P;Lips EH;Wessels LFA;de Visser KE
通讯作者：
de Visser KE
影响因子：
10.1
作者：
Kiss, Mate;Vande Walle, Lieselotte;Laoui, Damya
通讯作者：
Laoui, Damya
DOI：
10.1084/jem.20050915
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casares N;Pequignot MO;Tesniere A;Ghiringhelli F;Roux S;Chaput N;Schmitt E;Hamai A;Hervas-Stubbs S;Obeid M;Coutant F;Métivier D;Pichard E;Aucouturier P;Pierron G;Garrido C;Zitvogel L;Kroemer G
通讯作者：
Kroemer G