A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer
A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer
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DOI：
10.1186/s40425-018-0464-1
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发表时间：
2019-01-21
影响因子：
10.9
通讯作者：
Zippelius, Alfred
中科院分区：
文献类型：
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作者：
D'Amico, Lucia;Menzel, Ulrike;Zippelius, Alfred
越来越多的证据表明，抗体-药物偶联物（ADC）可以增强抗肿瘤免疫，改善临床结局。在这里，我们阐明了一种新型HER 2靶向ADC的治疗效果和免疫介导的机制，该ADC携带有效的蒽环类衍生物作为有效载荷（T-PNU），在对曲妥珠单抗和ado-曲妥珠单抗-美坦新偶联物耐药的人HER 2表达同基因乳腺癌模型中。从机制上讲，新型ADC的蒽环类药物组分诱导免疫原性细胞死亡，导致暴露和分泌TNF-α相关分子信号。RNA测序衍生的免疫基因组特征和肿瘤浸润淋巴细胞的TCR β克隆型分析揭示了适应性免疫系统在调节T-PNU介导的抗癌活性中的突出作用。CD 8 T细胞的消耗严重降低了T-PNU功效，从而证实了细胞毒性T细胞作为T-PNU介导的抗肿瘤免疫应答的驱动者的作用。此外，T-PNU治疗促进了荷瘤动物的免疫记忆形成，保护其免受肿瘤再攻击。最后，T-PNU和检查点抑制（如α-PD 1）的组合显著增强了治疗后的肿瘤根除。总之，新型PNU武装的HER 2靶向ADC在对其他HER 2靶向疗法耐药的鼠原位乳腺癌模型中引发了持久的免疫保护。我们的研究结果描述了这种新型ADC有效载荷的治疗潜力，并支持其在乳腺癌患者和其他可能表达HER 2的恶性肿瘤中的临床开发。
Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU) in a human HER2-expressing syngeneic breast cancer model resistant to trastuzumab and ado-trastuzumab emtansine. Mechanistically, the anthracycline component of the novel ADC induced immunogenic cell death leading to exposure and secretion of danger-associated molecular signals. RNA sequencing derived immunogenomic signatures and TCR beta clonotype analysis of tumor-infiltrating lymphocytes revealed a prominent role of the adaptive immune system in the regulation of T-PNU mediated anti-cancer activity. Depletion of CD8 T cells severely reduced T-PNU efficacy, thus confirming the role of cytotoxic T cells as drivers of the T-PNU mediated anti-tumor immune response. Furthermore, T-PNU therapy promoted immunological memory formation in tumor-bearing animals protecting those from tumor rechallenge. Finally, the combination of T-PNU and checkpoint inhibition, such as alpha-PD1, significantly enhanced tumor eradication following the treatment. In summary, a novel PNU-armed, HER2-targeting ADC elicited long-lasting immune protection in a murine orthotopic breast cancer model resistant to other HER2-directed therapies. Our findings delineate the therapeutic potential of this novel ADC payload and support its clinical development for breast cancer patients and potentially other HER2 expressing malignancies.