TIGIT as a therapeutic target of HPV-positive head and neck squamous cell carcinomas

The tumor immune microenvironment (TIME) of treatment-naive, human papillomavirus-positive head and neck squamous cell carcinoma (HPV-positive HNSCC) was interrogated at single-cell level to identify influential immune checkpoints as therapeutic targets. Single-cell transcriptome profiling revealed enrichment of numerous cell-cell interactions mediated by TIGIT-PVR/NECTIN2 in the TIME of HPV-positive HNSCC versus normal tonsil. TIGIT was the most differentially upregulated immune checkpoint on clonally expanded CD8+ T cells and was abundant on antigen-experienced, tissue-resident memory CD8+ T cell and T-regulatory subsets. TIGIT ligands PVR/NECTIN1/2 were abundant on mature regulatory dendritic cells (DCs), immunosuppressive plasmacytoid DCs, and macrophages. TIGIT and PD-1 co-blockade in the mEER murine model of HPV-positive HNSCC significantly reduced tumor growth, improved survival, restored effector function of HPV16 E7-specific CD8+ T cells, natural killer cells, and DCs, and conferred tumor re-challenge protection. This immunogenetic analysis at single-cell resolution focusing on HPV-positive HNSCC identified TIGIT as a rational therapeutic target.