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

Abstract

The tumor immune microenvironment (TIME) of treatment-naïve, 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, 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.

Novel Systemic Treatment Modalities Including Immunotherapy and Molecular Targeted Therapy for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma

“…Apart from PD-1, other T-cell exhaustion markers are also targets for ICI and are upregulated in HPV-positive HNSCC, such as cytotoxic T-lymphocyte protein 4 (CTLA4), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and lymphocyte activation gene 3 protein (LAG3) [ 183 , 184 ].…”