CD161 characterizes an inflamed subset of cytotoxic T lymphocytes and contributes to prolonged survival in human papillomavirus-driven oropharyngeal cancer

Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) is distinct from tobacco- or alcohol-associated OPSCC with unique immune landscape. However, the underlying phenotypic and functional differences of T cells remain unclear. We assessed the transcriptional profiles of single cells from intra-tumoral cell populations. Immune cells within tumors of HPV-positive and HPV-negative HNSCC displayed a spectrum of transcriptional signatures, with CD8+ T cells being relatively divergent. We identified CD161, which was encoded by KLRB1, was a marker to characterize a different evolutionary trajectory of partial CD8+ T cells. Further analysis revealed of that CD161+ CTLs but not CD161- CTLs revealed displayed a stronger immune activity with a T-cell inflamed phenotype, which could be reinvigorated by blocking checkpoints. Moreover, the level of CD161+ CTLs was associated with the treatment response and survival. Our work provided a new insight into the heterogeneity of immune microenvironment in OPSCC and also shed light on the potential target for immunotherapy.