UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
Sci Adv. 2023 Apr 14;9(15):eadd1992. doi: 10.1126/sciadv.add1992. Epub 2023 Apr 12.
While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors. In silico drug screening, supported by subsequent experimental testing, shows that treatment of primary tumors with MAPK pathway inhibitors may further prevent LC migration. In addition, our in silico model predicts treatment combinations that bypass LC dysfunction. In conclusion, our combined approach of in silico and in vivo studies suggests a molecular mechanism that explains how early melanomas develop under the radar of immune surveillance by LC.
虽然皮肤是一个活跃的免疫监视部位，但原发性黑色素瘤常常逃脱检测。在这里，我们开发了一种计算模型来确定黑色素瘤和朗格汉斯细胞（LC）之间的局部串扰，LC 是黑色素瘤发展部位的主要抗原呈递细胞。该模型预测，黑色素瘤不会激活 LC 迁移到淋巴结，直到肿瘤达到临界大小，这是由黑色素瘤内 TNF-α 正反馈回路决定的，与我们对小鼠肿瘤的观察结果一致。通过随后的实验测试支持的计算药物筛选表明，用 MAPK 通路抑制剂治疗原发性肿瘤可能进一步阻止 LC 迁移。此外，我们的计算模型还预测了可以绕过 LC 功能障碍的治疗组合。总之，我们的计算和体内研究相结合的方法提出了一个分子机制，解释了早期黑色素瘤如何在 LC 的免疫监视下悄然发展。
