Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
Stanford Cancer Institute, 265 Campus Drive, Ste G2103, Stanford, California 94305, USA.
Nat Commun. 2016 Dec 23;7:13898. doi: 10.1038/ncomms13898.
Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours. Profiling the tumours revealed that the Axl receptor tyrosine kinase is overexpressed in the unresponsive tumours, and Axl knockout resulted in slower growth and increased radiosensitivity. These changes were associated with a CD8 T-cell response, which was improved in combination with checkpoint immunotherapy. These results suggest a novel role for Axl in suppressing antigen presentation through MHCI, and enhancing cytokine release, which promotes a suppressive myeloid microenvironment.
越来越多的证据表明，离子射线治疗（RT）联合检查点免疫疗法在治疗某些癌症方面非常有效。为了更好地了解这种联合治疗的有限反应，我们分析了来源于转基因乳腺癌模型的肿瘤中的遗传、微环境和免疫因素。我们发现了两个具有相似生长特征但 RT 反应不同的肿瘤，主要是由于抗肿瘤免疫反应。RT 和检查点免疫疗法的联合治疗导致反应性肿瘤得到治愈，但非反应性肿瘤无效。对肿瘤的分析表明，在无反应性肿瘤中，Axl 受体酪氨酸激酶过度表达，Axl 敲除导致生长缓慢和放射敏感性增加。这些变化与 CD8 T 细胞反应相关，与检查点免疫疗法联合使用可改善这种反应。这些结果表明 Axl 通过 MHC I 抑制抗原呈递和增强细胞因子释放，从而促进抑制性髓样微环境，从而发挥了一种新的作用。
Zotero 插件
