Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, the Netherlands.
Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cell. 2018 Dec 13;175(7):1744-1755.e15. doi: 10.1016/j.cell.2018.10.028. Epub 2018 Nov 29.
Tumor-infiltrating CD8 T cells were found to frequently express the inhibitory receptor NKG2A, particularly in immune-reactive environments and after therapeutic cancer vaccination. High-dimensional cluster analysis demonstrated that NKG2A marks a unique immune effector subset preferentially co-expressing the tissue-resident CD103 molecule, but not immune checkpoint inhibitors. To examine whether NKG2A represented an adaptive resistance mechanism to cancer vaccination, we blocked the receptor with an antibody and knocked out its ligand Qa-1, the conserved ortholog of HLA-E, in four mouse tumor models. The impact of therapeutic vaccines was greatly potentiated by disruption of the NKG2A/Qa-1 axis even in a PD-1 refractory mouse model. NKG2A blockade therapy operated through CD8 T cells, but not NK cells. These findings indicate that NKG2A-blocking antibodies might improve clinical responses to therapeutic cancer vaccines.
肿瘤浸润 CD8 T 细胞经常表达抑制性受体 NKG2A，尤其是在免疫反应性环境中和癌症治疗性疫苗接种后。高维聚类分析表明，NKG2A 标志着一个独特的免疫效应子亚群，优先共表达组织驻留的 CD103 分子，但不表达免疫检查点抑制剂。为了研究 NKG2A 是否代表对癌症疫苗接种的适应性抵抗机制，我们用抗体阻断该受体，并在四种小鼠肿瘤模型中敲除其配体 Qa-1（HLA-E 的保守直系同源物）。即使在 PD-1 耐药的小鼠模型中，破坏 NKG2A/Qa-1 轴也极大地增强了治疗性疫苗的作用。NKG2A 阻断治疗通过 CD8 T 细胞起作用，但不通过 NK 细胞。这些发现表明，NKG2A 阻断抗体可能改善治疗性癌症疫苗的临床反应。
