脑转移发生于乳腺癌晚期，是乳腺癌患者死亡的主要原因。随着乳腺癌的颅外病变治疗不断改善，患者的生存期越来越长，脑转移的发生率也越来越高。2021年发表的荟萃分析表明，对于HER2阳性、三阴性、激素受体阳性HER2阴性的晚期乳腺癌患者，脑转移发生率分别达31%、32%和15%。乳腺癌脑转移对标准治疗大多低效，通常被认为无法治愈。虽然免疫治疗对许多癌症有效，但是尚未被成功用于乳腺癌脑转移，部分因为乳腺癌属于免疫细胞浸润较少的“冷”肿瘤，还因为血脑屏障为脑组织提供了独立的免疫环境。若干研究已经尝试将“冷”肿瘤容易对免疫治疗起效。例如，常规化疗可以显示免疫调节特性并且影响免疫反应。一方面，化疗可能改变癌细胞的免疫特性。另一方面，化疗也可直接影响免疫细胞的特性。利用化疗的免疫调节特性可将免疫细胞吸引至肿瘤部位并使“冷”肿瘤对免疫治疗敏感。除了杀死癌细胞，化疗还可诱发癌细胞进入衰老状态。重要的是，已知衰老细胞可通过分泌衰老相关因子触发肿瘤微环境以及肿瘤免疫重塑。此外，衰老和衰老相关因子对肿瘤微环境的免疫影响依赖于环境和肿瘤类型。不过，既往尚未研究化疗诱发细胞衰老对塑造乳腺癌脑转移灶免疫微环境的影响。 2022年11月15日，美国《细胞》旗下《细胞报告：医学》在线发表荷兰癌症研究所、乌得勒支大学医学中心、莱顿大学医学中心、哈格兰登医疗中心、英国曼彻斯特大学、美国哈佛大学医学院和麻省总医院的研究报告，重新利用蒽环类化疗药物多柔比星（商品名：阿霉素）促衰老特性将免疫治疗引入乳腺癌脑转移获得初步成功。 该研究利用PyMT和Neu乳腺肿瘤建立乳腺癌脑转移免疫活性小鼠模型，测试通过多柔比星促衰老特性启动乳腺癌脑转移特异性免疫微环境。 结果发现，多柔比星诱发乳腺癌脑转移细胞衰老可触发免疫细胞程序性死亡受体PD-1阳性T淋巴细胞向大脑集中。 重要的是，该研究证实多柔比星诱发癌细胞衰老通过CD8阳性T淋巴细胞可增强PD-1抑制剂免疫治疗对乳腺癌脑转移的效果，从而提供了将免疫治疗引入该致命病变的优化策略。 此外，该研究建立的乳腺癌脑转移模型还可用于将来其他治疗策略临床前测试。 因此，该研究结果表明，多柔比星可诱发乳腺癌脑转移灶衰老过程，乳腺癌脑转移灶衰老细胞又可将PD-1阳性T淋巴细胞吸引至乳腺癌脑转移灶，多柔比星预先治疗可增强乳腺癌脑转移免疫检查点抑制剂疗效，故有必要进一步开展临床研究进行验证。Cell Rep Med. 2022 Nov 15;3(11):100821. IF: 16.988Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis.Rebeca Uceda-Castro, Andreia S. Margarido, Lesley Cornet, Serena Vegna, Kerstin Hahn, Ji-Ying Song, Diana A. Putavet, Mariska van Geldorp, Ceren H. Citirikkaya, Peter L.J. de Keizer, Leon C. ter Beek, Gerben R. Borst, Leila Akkari, Olaf van Tellingen, Marike L.D. Broekman, Claire Vennin, Jacco van Rheenen.The Netherlands Cancer Institute, Amsterdam, the Netherlands; University Medical Center Utrecht, Utrecht, the Netherlands; Leiden University Medical Center, Leiden, the Netherlands; Haaglanden Medical Center, Lijnbaan, The Hague, the Netherlands; University of Manchester, Manchester, UK; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.- Generation of two mouse breast cancer brain metastasis (BCBM) models
- Doxorubicin induces a senescence program in BCBM
- Senescent cells in BCBM recruits PD1+ T cells to BCBM
- Doxorubicin pre-treatment improves immune checkpoint blockade in BCBM
An increasing number of breast cancer patients develop brain metastases (BM). Standard-of-care treatments are largely inefficient, and breast cancer brain metastasis (BCBM) patients are considered untreatable. Immunotherapies are not successfully employed in BCBM, in part because breast cancer is a “cold” tumor and also because the brain tissue has a unique immune landscape. Here, we generate and characterize immunocompetent models of BCBM derived from PyMT and Neu mammary tumors to test how harnessing the pro-senescence properties of doxorubicin can be used to prime the specific immune BCBM microenvironment. We reveal that BCBM senescent cells, induced by doxorubicin, trigger the recruitment of PD1-expressing T cells to the brain. Importantly, we demonstrate that induction of senescence with doxorubicin improves the efficacy of immunotherapy with anti-PD1 in BCBM in a CD8 T cell-dependent manner, thereby providing an optimized strategy to introduce immune-based treatments in this lethal disease. In addition, our BCBM models can be used for pre-clinical testing of other therapeutic strategies in the future.KEYWORDS: breast cancer brain metastasis, senescence, doxorubicin, T cells, mouse models, immune checkpoint blockadeDOI: 10.1016/j.xcrm.2022.100821
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