Li Xian-Yang, Corvino Dillon, Nowlan Bianca, Aguilera Amelia Roman, Ng Susanna S, Braun Matthias, Cillo Anthony R, Bald Tobias, Smyth Mark J, Engwerda Christian R
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Zhuhai Precision Medical Center, Zhuhai People's Hospital, Jinan University, Zhuhai, Guangdong, P.R. China.
Cancer Immunol Res. 2022 Feb;10(2):154-161. doi: 10.1158/2326-6066.CIR-20-0649. Epub 2022 Jan 10.
Tumor antigen-specific CD8 T cells play a critical role in antitumor immunity. Clinical trials reinvigorating the immune system via immune checkpoint blockade (ICB) have shown remarkable clinical promise. Numerous studies have identified an association between expression and patient outcome across different malignancies. However, aside from these correlative observations, very little is known about NKG7 and its role in antitumor immunity. Herein, we utilized single-cell RNA sequencing (scRNA-seq) datasets, -deficient mice, -reporter mice, and mouse tumor models to investigate the role of NKG7 in neoantigen-mediated tumor rejection and ICB immunotherapy. scRNA-seq of tumors from patients with metastatic melanoma or head and neck squamous cell carcinoma revealed that expression is highly associated with cytotoxicity and specifically expressed by CD8 T cells and natural killer (NK) cells. Furthermore, we identified a key role for NKG7 in controlling intratumor T-cell accumulation and activation. NKG7 was upregulated on intratumor antigen-specific CD8 T cells and NK cells and required for the accumulation of T cells in the tumor microenvironment. Accordingly, neoantigen-expressing mouse tumors grew faster in -deficient mice. Strikingly, efficacy of single or combination ICB was significantly reduced in -deficient mice.
肿瘤抗原特异性CD8 T细胞在抗肿瘤免疫中发挥关键作用。通过免疫检查点阻断（ICB）重振免疫系统的临床试验已显示出显著的临床前景。众多研究已确定在不同恶性肿瘤中其表达与患者预后之间存在关联。然而，除了这些相关性观察结果外，关于NKG7及其在抗肿瘤免疫中的作用知之甚少。在此，我们利用单细胞RNA测序（scRNA-seq）数据集、NKG7缺陷小鼠、NKG7报告基因小鼠和小鼠肿瘤模型来研究NKG7在新抗原介导的肿瘤排斥和ICB免疫治疗中的作用。对转移性黑色素瘤或头颈部鳞状细胞癌患者的肿瘤进行scRNA-seq分析发现，NKG7表达与细胞毒性高度相关，且特异性地由CD8 T细胞和自然杀伤（NK）细胞表达。此外，我们确定了NKG7在控制肿瘤内T细胞积聚和激活中的关键作用。NKG7在肿瘤内抗原特异性CD8 T细胞和NK细胞上上调，是肿瘤微环境中T细胞积聚所必需的。因此，表达新抗原的小鼠肿瘤在NKG7缺陷小鼠中生长更快。令人惊讶的是，NKG7缺陷小鼠中单一或联合ICB的疗效显著降低。
