自然杀伤 (NK) 细胞的激活和抑制受体（例如 NKp、NKG2 或 CLEC）与包括胶质母细胞瘤 (GBM) 在内的冷肿瘤高度相关。在这里，我们的目的是表征这些受体在 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。我们对几种 NK 受体进行了转录组分析，重点关注由 KLRC2、NKG2C 等编码的激活受体批量和单细胞 RNA 测序 GBM 数据集。我们还评估了过表达 KLRC2 的 GL261 细胞对使用或不使用程序性细胞死亡蛋白 1 (PD-1) 单克隆抗体 (mAb) 治疗的小鼠的影响。最后，我们分析了两项评估 PD-1 mAb 对 GBM 患者效果的临床试验的样本，以确定 NKG2C 作为反应生物标志物的潜力。我们观察到 GBM 浸润 NK 和 T 细胞上几种抑制性 NK 受体的显着表达，这与肿瘤细胞上 KLRC2 的强表达（主要在浸润边缘）形成对比。肿瘤性 KLRC2 表达与骨髓源性抑制细胞数量减少和肿瘤驻留淋巴细胞水平升高相关。在小鼠模型和 GBM 患者的 NKG2C 高表达肿瘤中观察到，PD-1 mAb 治疗后具有更强的抗肿瘤活性，而抑制性 NK 受体的表达呈负相关。本研究探讨了肿瘤性 NKG2C/KLRC2 表达在塑造中的作用GBM 的免疫特征，表明它是 GBM 患者对免疫检查点抑制剂治疗产生阳性反应的预测生物标志物。未来的研究可以在前瞻性试验中进一步验证这一发现。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

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.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.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.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.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.