Liu Shang-Xin, Wu Tao-Wei, Luo Dong-Hua, Zhang Le-Le, Zhou Lu, Luo Yi-Ling, Du Wen-Ting, Huang Ting-Ting, Jiang Sizun, Zhang Zhe, Han Ping, Zeng Mu-Sheng, Zhong Qian
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, P.R. China.
Cell Rep Med. 2025 Jul 15;6(7):102200. doi: 10.1016/j.xcrm.2025.102200. Epub 2025 Jun 20.
The outcome of immune checkpoint blockade (ICB) therapy largely hinges on the antitumor immunity of tertiary lymphoid structures (TLSs), but drivers of tumor TLS formation remain exclusive. By integrating spatial transcriptomics and a pan-cancer single-cell atlas, we reveal the characteristics of TLSs in nasopharyngeal carcinoma (NPC) and identify a subset of interferon-responsive high endothelial venules (IFN-HEVs) that links to the emergence of tumor-specific chemokines, especially CXCL9. Functionally, CXCL9-secreting IFN-HEVs are associated with the recruitment of CXCR3CD4 T cells into TLSs. IFN-HEV-related phenotypes are strongly correlated with prolonged survival and enhanced ICB responsiveness. Leveraging these phenotypes, we develop a pretreatment CXCL9-TLS response-predictive scoring system (CTRscore), which robustly forecasts ICB therapeutic outcomes in three independent NPC cohorts. Our study provides biological and functional insights into the IFN-HEVs in tumor TLSs, highlighting their potential role in the development of biomarkers and predictors for the success of ICB therapy.
免疫检查点阻断（ICB）疗法的疗效很大程度上取决于三级淋巴结构（TLS）的抗肿瘤免疫力，但肿瘤TLS形成的驱动因素仍然未知。通过整合空间转录组学和泛癌单细胞图谱，我们揭示了鼻咽癌（NPC）中TLS的特征，并鉴定出一组干扰素反应性高内皮微静脉（IFN-HEV），它们与肿瘤特异性趋化因子尤其是CXCL9的出现有关。在功能上，分泌CXCL9的IFN-HEV与CXCR3⁺CD4⁺ T细胞募集到TLS中有关。IFN-HEV相关表型与生存期延长和ICB反应性增强密切相关。利用这些表型，我们开发了一种治疗前CXCL9-TLS反应预测评分系统（CTRscore），该系统能够可靠地预测三个独立NPC队列中的ICB治疗结果。我们的研究为肿瘤TLS中的IFN-HEV提供了生物学和功能方面的见解，突出了它们在开发ICB治疗成功的生物标志物和预测指标方面的潜在作用。
