Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.
Front Immunol. 2023 Feb 13;14:1124066. doi: 10.3389/fimmu.2023.1124066. eCollection 2023.
Epstein-Barr virus (EBV) DNA seronegative (Sero-) and seropositive (Sero+) nasopharyngeal carcinoma (NPC) are distinctly different disease subtypes. Patients with higher baseline EBV DNA titers seem to benefit less from anti-PD1 immunotherapy, but underlying mechanisms remain unclear. Tumor microenvironment (TME) characteristics could be the important factor affecting the efficacy of immunotherapy. Here, we illuminated the distinct multicellular ecosystems of EBV DNA Sero- and Sero+ NPCs from cellular compositional and functional perspectives at single-cell resolution.
We performed single-cell RNA sequencing analyses of 28,423 cells from ten NPC samples and one non-tumor nasopharyngeal tissue. The markers, function, and dynamics of related cells were analyzed.
We found that tumor cells from EBV DNA Sero+ samples exhibit low-differentiation potential, stronger stemness signature, and upregulated signaling pathways associated with cancer hallmarks than that of EBV DNA Sero- samples. Transcriptional heterogeneity and dynamics in T cells were associated with EBV DNA seropositivity status, indicating different immunoinhibitory mechanisms employed by malignant cells depending on EBV DNA seropositivity status. The low expression of classical immune checkpoints, early-triggered cytotoxic T-lymphocyte response, global activation of IFN-mediated signatures, and enhanced cell-cell interplays cooperatively tend to form a specific immune context in EBV DNA Sero+ NPC.
Collectively, we illuminated the distinct multicellular ecosystems of EBV DNA Sero- and Sero+ NPCs from single-cell perspective. Our study provides insights into the altered tumor microenvironment of NPC associated with EBV DNA seropositivity, which will help direct the development of rational immunotherapy strategies.
EB 病毒（EBV）DNA 阴性（Sero-）和阳性（Sero+）鼻咽癌（NPC）是明显不同的疾病亚型。基线 EBV DNA 滴度较高的患者似乎从抗 PD1 免疫治疗中获益较少，但潜在机制尚不清楚。肿瘤微环境（TME）特征可能是影响免疫治疗效果的重要因素。在这里，我们从细胞组成和功能角度，以单细胞分辨率阐明了 EBV DNA Sero-和 Sero+ NPC 的不同多细胞生态系统。
我们对来自十个 NPC 样本和一个非肿瘤鼻咽组织的 28423 个细胞进行了单细胞 RNA 测序分析。分析了相关细胞的标志物、功能和动态。
我们发现 EBV DNA Sero+样本的肿瘤细胞表现出低分化潜能、更强的干性特征以及上调与癌症标志相关的信号通路，这比 EBV DNA Sero-样本更为明显。T 细胞中的转录异质性和动态与 EBV DNA 血清阳性状态相关，表明恶性细胞根据 EBV DNA 血清阳性状态采用不同的免疫抑制机制。经典免疫检查点的低表达、早期触发的细胞毒性 T 淋巴细胞反应、IFN 介导的特征的全局激活以及增强的细胞间相互作用共同倾向于在 EBV DNA Sero+ NPC 中形成特定的免疫环境。
总之，我们从单细胞角度阐明了 EBV DNA Sero-和 Sero+ NPC 的不同多细胞生态系统。我们的研究为与 EBV DNA 血清阳性相关的 NPC 中改变的肿瘤微环境提供了深入了解，这将有助于指导合理的免疫治疗策略的制定。
