Zhang Yuying, Li Jinbang, Guo Xiaoyu, Gao Zhao, Pan Junchen, Nong Sheng, Ma Jiyuan, Chen Gang, Zhang Jiali
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Department of Oral Pathology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Cancer Res. 2025 Sep 2;85(17):3258-3274. doi: 10.1158/0008-5472.CAN-24-4383.
Neoadjuvant immunotherapy is a first-line treatment for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC). However, only a fraction of patients with advanced HNSCC benefit from immunotherapy. Identifying accurate and accessible biomarkers is essential for optimal patient selection. In this study, we integrated single-cell RNA sequencing and T-cell receptor sequencing to comprehensively characterize the tumor immune microenvironment (TIME) of HNSCC biopsies prior to a phase II neoadjuvant immunotherapy clinical trial. Tumor-specific MHC-II (tsMHC-II) was identified as a superior predictor of response to neoadjuvant immunotherapy in HNSCC compared with PD-L1. Mechanistically, tsMHC-II ignited a hot TIME and enhanced the effect of PD-1 blockade by recruiting T cells through the induction of chemokines, particularly CCL5. Moreover, tsMHC-II triggered a Th1 response and activated CD4+ and CD8+ T-cell expansion, suppressing HNSCC growth in a CD4+ T-cell-dependent manner. Simultaneously, tsMHC-II facilitated an increase in PD-1+CD4+ T cells and a modest elevation in tumor PD-L1, thereby enhancing sensitivity to anti-PD-1 therapy. This study highlights that tsMHC-II, by generating an inflamed TIME, is crucial in enhancing the effectiveness of neoadjuvant immunotherapy in HNSCC.
scRNA-seq analysis identifies tumor-specific MHC-II as a predictor for neoadjuvant immunotherapy response in HNSCC and provides insights into the complex networks that ignite a hot tumor immune microenvironment and regulate T-cell infiltration.
新辅助免疫疗法是复发性和转移性头颈部鳞状细胞癌（HNSCC）的一线治疗方法。然而，只有一小部分晚期HNSCC患者能从免疫疗法中获益。识别准确且易于获取的生物标志物对于优化患者选择至关重要。在本研究中，我们整合了单细胞RNA测序和T细胞受体测序，以全面表征II期新辅助免疫疗法临床试验前HNSCC活检样本的肿瘤免疫微环境（TIME）。与程序性死亡受体配体1（PD-L1）相比，肿瘤特异性主要组织相容性复合体II类分子（tsMHC-II）被确定为HNSCC新辅助免疫疗法反应的更优预测指标。从机制上讲，tsMHC-II通过诱导趋化因子（特别是CCL5）募集T细胞，从而引发一个活跃的TIME并增强程序性死亡受体1（PD-1）阻断的效果。此外，tsMHC-II引发辅助性T细胞1（Th1）反应并激活CD4+和CD8+ T细胞扩增，以CD4+ T细胞依赖的方式抑制HNSCC生长。同时，tsMHC-II促进PD-1+CD4+ T细胞增加以及肿瘤PD-L1适度升高，从而增强对抗PD-1治疗的敏感性。本研究强调，tsMHC-II通过产生炎症性TIME，在增强HNSCC新辅助免疫疗法的有效性方面至关重要。
单细胞RNA测序分析确定肿瘤特异性MHC-II为HNSCC新辅助免疫疗法反应的预测指标，并深入了解引发活跃肿瘤免疫微环境和调节T细胞浸润的复杂网络。
