Translational Tumor Immunology Group, Ludwig Center for Cancer Research of the University of Lausanne, Lausanne, Switzerland.
Cancer Res. 2011 Mar 1;71(5):1607-14. doi: 10.1158/0008-5472.CAN-10-3490. Epub 2011 Feb 22.
The discovery of a targeted therapeutic compound along with its companion predictive biomarker is a major goal of clinical development for a personalized anticancer therapy to date. Here we present evidence of the predictive value of TLR3 expression by tumor cells for the efficacy of Poly (A:U) dsRNA in 194 breast cancer patients enrolled in a randomized clinical trial. Adjuvant treatment with double-stranded RNA (dsRNA) was associated with a significant decrease in the risk of metastatic relapse in TLR3 positive but not in TLR3-negative breast cancers. Moreover, we show the functional relevance of TLR3 expression by human tumor cells for the antitumor effects mediated by dsRNA in several preclinical mouse models carried out in immunocompromised animals. These 2 independent lines of evidence relied upon the generation of a novel tool, an anti-TLR3 antibody (40F9.6) validated for routine detection of TLR3 expression on paraffin-embedded tissues. Altogether, these data suggest that dsRNA mediates its therapeutic effect through TLR3 expressed on tumor cells, and could therefore represent an effective targeted treatment in patients with TLR3-positive cancers.
迄今为止，针对癌症的个体化治疗的临床开发的主要目标之一是发现靶向治疗化合物及其伴随的预测性生物标志物。在这里，我们提出了肿瘤细胞 TLR3 表达对聚（A：U）dsRNA 在 194 名入组随机临床试验的乳腺癌患者中的疗效的预测价值的证据。dsRNA 的辅助治疗与 TLR3 阳性但 TLR3 阴性乳腺癌的转移复发风险显著降低相关。此外，我们展示了 TLR3 表达的功能性相关性通过 dsRNA 在几种免疫缺陷动物中进行的临床前小鼠模型中的抗肿瘤作用。这 2 条独立的证据线依赖于一种新型工具的产生，即抗 TLR3 抗体（40F9.6），该抗体已通过常规检测石蜡包埋组织中 TLR3 的表达进行了验证。总之，这些数据表明 dsRNA 通过肿瘤细胞上表达的 TLR3 介导其治疗效果，因此可能代表 TLR3 阳性癌症患者的有效靶向治疗方法。
