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接种ALK肽可恢复ALK重排非小细胞肺癌的免疫原性

原文发布日期：2023-07-10

英文摘要：

摘要翻译：

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文章：

接种ALK肽可恢复ALK重排非小细胞肺癌的免疫原性

ALK peptide vaccination restores the immunogenicity of ALK-rearranged non-small cell lung cancer

原文发布日期：2023-07-10

英文摘要：

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is treated with ALK tyrosine kinase inhibitors (TKIs), but the lack of activity of immune checkpoint inhibitors (ICIs) is poorly understood. Here, we identified immunogenic ALK peptides to show that ICIs induced rejection of ALK+ tumors in the flank but not in the lung. A single-peptide vaccination restored priming of ALK-specific CD8+ T cells, eradicated lung tumors in combination with ALK TKIs and prevented metastatic dissemination of tumors to the brain. The poor response of ALK+ NSCLC to ICIs was due to ineffective CD8+ T cell priming against ALK antigens and is circumvented through specific vaccination. Finally, we identified human ALK peptides displayed by HLA-A*02:01 and HLA-B*07:02 molecules. These peptides were immunogenic in HLA-transgenic mice and were recognized by CD8+ T cells from individuals with NSCLC, paving the way for the development of a clinical vaccine to treat ALK+ NSCLC.

摘要翻译：

ALK突变的非小细胞肺癌通过ALK激酶抑制剂进行治疗，但免疫检查点抑制剂（ICIs）缺乏活性的原因尚不明确。在这里，我们通过免疫原性ALK肽证明了免疫检查点抑制剂诱导了ALK阳性肿瘤在侧带部位的排斥，但对肺癌没有这样的作用。单种抗原疫苗恢复了对ALK特定的CD8+ T细胞的刺激，在联合使用ALK激酶抑制剂的同时消灭了肺癌，并阻止了肿瘤向大脑等远处转移。ALK阳性非小细胞肺癌对ICIs的不良反应是因为对ALK抗原缺乏有效的CD8+ T细胞刺激，通过疫苗接种得以绕过这一缺陷。最后我们鉴定到HLA-A*02:01和HLA-B*07:02分子上展示的人类ALK肽。这些肽在特定的HLA-转基因小鼠中是免疫原性的，并被携带者中有肺癌的CD8+ T细胞所识别，为治疗ALK阳性非小细胞肺癌开发临床疫苗铺平了道路。