Immune cell phenotypes of head and neck lesions associated with viral infections

Abstract: Tonsillar cancer (TC) and nasopharyngeal cancer (NPC) are associated with high-risk humanpapillomavirus (HPV) and Epstein-Barr virus (EBV), respectively. Similarly, benign lesions, knownas laryngeal papilloma (LP), are associated with low-risk HPV. Recent advances have includedimmunotherapy as a part of the treatment regimen for recurrent and metastatic HNC and LP,although with limited response rates.An in-depth understanding of the genetics of the lesions and molecular underpinnings hasidentified molecular changes that may guide patient care. In papers I-III, key immune players,including CD8+ T cells and antigen-presenting cells (APCs), were studied in NPC and TC. Usingquantitative density of CD8+ T cells in NPC, three phenotypes were defined: "inflamed", "immune-excluded", and "desert". Based on CD8+ T cells infiltratrion, the inflamed phenotype wasassociated with higher survival rates than the "immune-excluded".In paper II, digital spatial technology was used to further investigate the defined phenotypes.Higher median expression of protein markers such as CD11c and IDO1 and lower medianexpression of fibronectin in NPC stromal regions were associated with improved survival. In paperIII, we demonstrated a correlation between the levels of APCs and CD8+ T cells in HPV+ TC, andshowed that patients with high levels of CD8 transcripts had improved survivalIn papers IV-V, we investigated LP using gene expression and flow cytometry and observed aninverse relationship between CD8+ T cells and neutrophils. In addition, a streptococcus subspecieswas associated with severe clinical symptoms and high neutrophil counts in chronic LP (paper V:a case report). These findings provide a basis for further investigations of neutrophil and bacterialassociations in HPV-associated lesions.In conclusion, the cell types and biomarkers investigated in this thesis highlight the immuneheterogeneity of NPC, TC, and LP. Validations in larger patient cohorts are needed to developclinically applicable biomarkers for prognostics and patient stratification.