Distinct NK Cell Signatures Define Prognosis in HPV-Positive Versus HPV-Negative Head and Neck Cancer

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Human papillomavirus (HPV) status significantly impacts head and neck squamous cell carcinoma (HNSCC) prognosis.
• The underlying immunological mechanisms for HPV-positive (HPV+) versus HPV-negative (HPV-) HNSCC survival differences are not well understood.
• Characterizing tumor-infiltrating natural killer (NK) cells is crucial for identifying therapeutic targets.

Purpose of the Study:

• To analyze the NK cell landscape in HPV-stratified HNSCC.
• To identify NK cell subsets associated with HPV status and patient survival.
• To uncover novel therapeutic targets for HNSCC immunotherapy.

Main Methods:

• Re-analysis of single-cell RNA sequencing data from HNSCC patients stratified by HPV status.
• Identification of NK cell subsets and pseudotime trajectory inference.
• Cell-cell interaction analysis, immunohistochemistry validation, and TCGA data assessment for prognostic associations.

Main Results:

• Four distinct NK cell subsets were identified: adaptive, cell-killing, CD56bright, and virus-responsive.
• A cytotoxic CX3CR1+KLRB1dim NK subset was enriched in HPV+ HNSCC and linked to favorable survival.
• HPV- HNSCC exhibited upregulated CLEC2C/CLEC2D ligands, engaging KLRB1 on NK cells, correlating with suppressed NK activity and poorer prognosis.

Conclusions:

• NK cell function in HNSCC is dichotomously regulated by HPV status.
• The CX3CR1+KLRB1dim NK cell subset is a potential prognostic biomarker for HPV+ HNSCC.
• The CLEC2-KLRB1 axis represents a targetable immune evasion mechanism in HPV- HNSCC, suggesting HPV-stratified immunotherapy development.