Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Immune checkpoint inhibitors (ICIs) show efficacy in some head and neck squamous cell carcinoma (HNSCC) patients.
• Lack of robust predictive biomarkers limits the application of ICIs in HNSCC.

Purpose of the Study:

• To identify biomarkers associated with response to immune checkpoint inhibition in HNSCC.
• To investigate the role of APOBEC3-associated mutations in the tumor immune microenvironment of HNSCC.

Main Methods:

• Analysis of whole exome and RNA-sequencing data from TCGA and DKTK MASTER cohorts (n=506).
• Reanalysis of public single-cell RNA-sequencing data from HPV-negative HNSCC.
• Assessment of viral status, gene expression signatures, mutational load, and mutational signatures.

Main Results:

• APOBEC3-associated mutations, not overall mutational burden, correlated with inflammation in HPV-negative HNSCC.
• An APOBEC3-enriched subgroup of HPV-negative HNSCC exhibited increased T-cell inflammation, immune checkpoint expression, and APOBEC3 gene expression.
• Mutations in immune-evasion pathways were more frequent in this subgroup.
• Single-cell analysis confirmed APOBEC3B and 3C expression in malignant cells.

Conclusions:

• An APOBEC3-enriched subgroup of HPV-negative HNSCC possesses a distinct immunogenic phenotype.
• This phenotype, characterized by heightened inflammation and immune marker expression, may predict response to immunotherapy in HNSCC.