J Immunother Cancer:浙大黄建团队提出三阴性乳腺癌肺转移免疫学新机制及其干预策略

2021-12-12 “生物世界”公众号 “生物世界”公众号

乳腺癌是目前发病率最高的恶性肿瘤。随着乳腺癌“在筛早诊早治”推进,精准综合治疗的推广,其生存率已极大提升。尽管如此,三阴性乳腺癌 (TNBC) 由于缺乏相关预测指标和有效针对性的治疗手段。

乳腺癌是目前发病率最高的恶性肿瘤。随着乳腺癌“在筛早诊早治”推进,精准综合治疗的推广,其生存率已极大提升。尽管如此,三阴性乳腺癌 (TNBC) 由于缺乏相关预测指标和有效针对性的治疗手段,仍然是目前临床转化研究面临的难点和热点。

目前对于三阴性乳腺癌转移的机制众说纷纭,探索三阴性乳腺癌远处转移的新机制并探究行之有效的干预策略是目前领域内的研究方向,也是临床治疗上亟需突破的关键。肺是三阴性乳腺癌最常见的远处转移器官之一,然而其器官转移特异性及具体机制仍覆着一层神秘面纱待学者揭示。

近日,浙江大学医学院附属第二医院黄建教授团队在 Journal for Immunotherapy of Cancer 期刊发表了题为:Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis 的研究论文。

该研究表明,衰老中性粒细胞通过线粒体依赖的非致死性胞外捕获网(vNETs)促进乳腺癌肺转移,发现了乳腺癌肺转移的免疫学新机制并提出了针对性干预策略。

研究团队重点从三阴性乳腺癌肺转移着手,发现一群新型肿瘤相关衰老中性粒细胞(tumor-associated aged neutrophil, Naged;CXCR4+ CD62Llow Neutrophils)在肺转移前微环境 (Pre-metastatic niche) 中聚集,并通过形成线粒体依赖的vNETs捕捉循环肿瘤细胞,促进循环肿瘤细胞在肺组织局部停留,最终形成乳腺癌肺转移。

既往研究表明中性粒细胞在乳腺癌转移中发挥重要作用,但促转移和抑转移的功能均有报道,提示中性粒细胞的异质性是其功能差异的重要原因。黄建教授团队以206例人新鲜乳腺疾病患者样本和小鼠多种乳腺癌模型入手,发现中性粒细胞新亚群-Naged在三阴性乳腺癌患者和小鼠乳腺癌模型的外周血与肺组织中显着富集;还发现Naged的细胞核呈过分叶的衰老状态,形成了以SIRT1为核心的独特的转录组特征。Naged不同于PMN-MDSC(粒细胞样髓源系免疫抑制细胞),它不具备强免疫抑制功能,反而具有强胞外捕获网(NETs)的形成能力。深入机制层面研究进一步发现SIRT1是维持中性粒细胞衰老的关键因素,并通过开启线粒体膜通透性转换孔(mPTP)促进线粒体DNA的释放,引起线粒体依赖的vNETs形成。

模式图:原发肿瘤分泌NAMPT可以诱导外周血中性粒细胞极化为衰老中性粒细胞并募集于肺组织,衰老中性粒细胞中SIRT1显着上调,促进细胞核过分叶并形成线粒体依赖的胞外捕获网,捕捉循环肿瘤细胞形成肺转移。

这一全新的vNETs形成机制,让中性粒细胞的研究和认识更深入。此外,团队还发现,肿瘤分泌的NAMPT蛋白是诱导衰老中性粒细胞SIRT1激活的关键因子,也是促进乳腺癌肺转移的重要因素。为此,研究团队进一步发现应用SIRT1的广谱抑制剂Vit B3可有效阻断小鼠体内衰老中性粒细胞产生并显着减少乳腺癌肺转移发生。

该研究有望为后续预测乳腺癌患者肺转移提供新标记,为临床防治乳腺癌肺转移提供新策略。

浙江大学医学院附属第二医院常务副院长、乳腺外科学科带头人、浙江省肿瘤微环境与免疫治疗重点实验室主任黄建教授黄建教授作为通讯作者,浙江大学博士生杨承慧、王震和李丽丽为共同第一作者。

原始出处:

Chenghui Yang, et al. Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis. Journal for Immunotherapy of Cancer, 2021.

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  4. 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    2021-12-28 1501f26940m

    优秀

    0

  5. 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    2021-12-20 ms5000000275821148

    学习

    0

  6. 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    2021-12-14 xlysu
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  8. 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  9. 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    2021-12-13 **rain

    1

    0

  10. 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    2021-12-12 ms1000000203803067

    学到了

    0

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为何这队列中男性乳腺癌风险激增!只因他们都上夜班……

Breast Cancer Res:挪威海上石油工人(NOPW)的男性乳腺癌风险过高:可能与极端夜班工作有关吗?

Clin Cancer Res:HER2双特异性抗体KN026单药治疗HER2+转移性乳腺癌的临床试验结果

HER2双特异性抗体KN026在转移性乳腺癌患者中的耐受性良好,治疗效果堪比曲妥珠单抗和帕妥珠单抗双重治疗

J Clin Oncol:早期乳腺癌的内分泌治疗中加用帕博西利的效果

内分泌治疗中加用帕博西尼是否可进一步改善激素受体阳性乳腺癌的预后?

NEJM:绝经状态会影响腋窝淋巴结阳性乳腺癌患者化疗-内分泌联合治疗收益

对于存在1-3个阳性腋窝淋巴结的绝经前乳腺癌患者,化学内分泌联合治疗可显著提高患者无侵袭性疾病生存期,但绝经后患者化学内分泌联合治疗的收益不显著