ALK 肽疫苗接种恢复了 ALK 重排的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.
机构信息
Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
出版信息
Nat Cancer. 2023 Jul;4(7):1016-1035. doi: 10.1038/s43018-023-00591-2. Epub 2023 Jul 10.
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-A02:01 and HLA-B07:02 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.
间变性淋巴瘤激酶(ALK)重排的非小细胞肺癌(NSCLC)采用 ALK 酪氨酸激酶抑制剂(TKI)治疗,但免疫检查点抑制剂(ICI)缺乏活性的机制尚不清楚。在这里,我们鉴定了免疫原性的 ALK 肽,以表明 ICI 诱导了侧翼ALK 肿瘤的排斥,但对肺部的肿瘤没有作用。单一肽疫苗恢复了 ALK 特异性 CD8 T 细胞的激活,与 ALK TKI 联合根除了肺部肿瘤,并防止了肿瘤向大脑的转移扩散。ALK NSCLC 对 ICI 的反应不佳是由于针对 ALK 抗原的 CD8 T 细胞激活无效,而通过特异性疫苗接种可以避免这种情况。最后,我们鉴定了人 HLA-A02:01 和 HLA-B07:02 分子呈递的 ALK 肽。这些肽在 HLA 转基因小鼠中具有免疫原性,并被 NSCLC 患者的 CD8 T 细胞识别,为开发治疗 ALK NSCLC 的临床疫苗铺平了道路。