背景:激活和抑制自然杀伤(NK)细胞的受体,如NKp,NKG2或CLEC与冷肿瘤(包括成胶质细胞瘤(GBM))高度相关。这里,我们旨在表征这些受体在GBM中的表达,以深入了解它们作为肿瘤内微环境调节剂的潜在作用。
方法:我们对几种NK受体进行了转录组学分析,重点是由KLRC2,NKG2C编码的激活受体,在批量和单细胞RNA测序GBM数据集之间。我们还评估了KLRC2过表达的GL261细胞在用或不用程序性细胞死亡蛋白-1(PD-1)单克隆抗体(mAb)处理的小鼠中的作用。最后,我们分析了两项评估PD-1mAb在GBM患者中作用的临床试验的样本,以确定NKG2C作为应答生物标志物的潜力.
结果:我们观察到几种抑制性NK受体在GBM浸润NK和T细胞上的显著表达,这与KLRC2在肿瘤细胞上的强表达相反,主要在渗透边缘。肿瘤性KLRC2表达与骨髓来源的抑制细胞数量减少和肿瘤驻留淋巴细胞水平升高有关。在小鼠模型和GBM患者中,在表达NKG2Chigh的肿瘤中观察到PD-1mAb治疗后具有更强的抗肿瘤活性,而抑制性NK受体的表达显示出负相关。
结论:本研究探讨了肿瘤NKG2C/KLRC2表达在塑造GBM免疫谱中的作用,并表明它是GBM患者对免疫检查点抑制剂治疗阳性反应的预测性生物标志物。未来的研究可以在前瞻性试验中进一步验证这一发现。
BACKGROUND: Activating and inhibitory receptors of natural killer (NK) cells such as NKp, NKG2, or CLEC are highly relevant to cold tumors including glioblastoma (GBM). Here, we aimed to characterize the expression of these receptors in GBM to gain insight into their potential role as modulators of the intratumoral microenvironment.
METHODS: We performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded by KLRC2, NKG2C, among bulk and single-cell RNA sequencing GBM data sets. We also evaluated the effects of KLRC2-overexpressing GL261 cells in mice treated with or without programmed cell death protein-1 (PD-1) monoclonal antibody (mAb). Finally, we analyzed samples from two clinical trials evaluating PD-1 mAb effects in patients with GBM to determine the potential of NKG2C to serve as a biomarker of response.
RESULTS: We observed significant expression of several inhibitory NK receptors on GBM-infiltrating NK and T cells, which contrasts with the strong expression of KLRC2 on tumor cells, mainly at the infiltrative margin. Neoplastic KLRC2 expression was associated with a reduction in the number of myeloid-derived suppressor cells and with a higher level of tumor-resident lymphocytes. A stronger antitumor activity after PD-1 mAb treatment was observed in NKG2Chigh-expressing tumors both in mouse models and patients with GBM whereas the expression of inhibitory NK receptors showed an inverse association.
CONCLUSIONS: This study explored the role of neoplastic NKG2C/KLRC2 expression in shaping the immune profile of GBM and suggests that it is a predictive biomarker for positive responses to immune checkpoint inhibitor treatment in patients with GBM. Future studies could further validate this finding in prospective trials.