Tumor-Specific MHC-II Activates CD4+ and CD8+ T Cells in Head and Neck Squamous Cell Carcinoma to Boost Immunotherapy Efficacy

Abstract 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. Significance: 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.