1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [4] Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France.
Nat Med. 2014 Nov;20(11):1301-9. doi: 10.1038/nm.3708. Epub 2014 Oct 26.
Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.
一些蒽环类药物在小鼠中的抗肿瘤作用源于先天和 T 细胞介导的抗肿瘤免疫反应的诱导。在这里，我们证明蒽环类药物在模式识别受体 Toll 样受体 3 (TLR3) 被激活后，刺激恶性细胞快速产生 I 型干扰素 (IFN)。I 型 IFNs 通过与肿瘤细胞上的 IFN-α 和 IFN-β 受体 (IFNAR) 结合，触发自分泌和旁分泌回路，导致趋化因子 (C-X-C 基序) 配体 10 (CXCL10) 的释放。缺乏 Tlr3 或 Ifnar 的肿瘤如果不人为地提供 I 型 IFN 或 Cxcl10，则无法对化疗产生反应。此外，I 型 IFN 相关特征可预测几批具有不良预后的乳腺癌患者接受基于蒽环类药物的化疗的临床反应。我们的数据表明，蒽环类药物介导的免疫反应类似于病毒病原体诱导的免疫反应。我们推测这种“病毒模拟”是化疗成功的标志。
