Differences in cellular composition and molecular phenotype between HPV-related and non-HPV-related head and neck cancers

doi:10.19438/j.cjoms.2025.03.005

Abstract

Abstract: PURPOSE: To investigate the differences in tumor microenvironment and molecular phenotype between human papillomavirus (HPV)-related (HPV+) and non-HPV-related (HPV-) head and neck cancers (HNC). METHODS: Genomic, transcriptomic, and proteomic sequencing data for HNC were obtained from the TCGA public database via open-access platforms such as cbioportal. The patients were categorized into HPV+ and HPV- group based on HPV infection status. First, the CIBERSORTx cell-type deconvolution algorithm was applied to transcriptomic data to estimate differences in cellular composition between HPV+ and HPV- HNC. Subsequently, genomic, transcriptomic, and proteomic data were analyzed to identify genes with significantly increased mutation frequencies, enriched pathways, and upregulated proteins in HPV+ HNC compared to HPV- HNC. RESULTS: Significant differences were observed between HPV+ and HPV- HNC. ①Cellular composition: HPV+ tumors exhibited significantly higher infiltration of B cells, CD4⁺ T cells, and dendritic cells. ②Multi-omics alterations: genes such as CCM2L, CBFA2T2, and NECAB3 showed higher mutation frequencies in HPV+ tumors. The neuroactive ligand-receptor interaction pathway was significantly enriched in HPV+ tumors, proteins such as CLDN7 and SYK displayed higher expression levels in HPV+ tumors. ③FADS1 and ELF3 potentially participated in or regulated the phenotypic evolution of HPV+ HNC. FADS1 was a potential interacting protein of HPV16 E2, while ELF3 was a transcription factor specifically expressed in HPV+ epithelial tissues. Both genes exhibited a significant positive correlation with the gene set associated with the neuroactive ligand-receptor interaction pathway. CONCLUSIONS: Compared to HPV- HNC, the distribution of microenvironmental cell subtypes and potential regulatory elements in HPV+ HNC is significantly different, characterized by a higher proportion of immune cells and enrichment in pathways related to neural signaling and immune response.

Key words: Head and neck cancer, Human papillomavirus, Tumor microenvironment, Genetic alterations, Neuro-related pathways

CLC Number:

R739.8

Xue Pengxin, Sun Lulu, Sun Shuyang. Differences in cellular composition and molecular phenotype between HPV-related and non-HPV-related head and neck cancers[J]. China Journal of Oral and Maxillofacial Surgery, 2025, 23(3): 236-243.

References

[1] Lechner M, Liu J, Masterson L, et al.HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management[J]. Nat Rev Clin Oncol, 2022, 19(5): 306-327.
[2] Zamani M, Grϕnhϕj C, Jensen DH, et al.The current epidemic of HPV-associated oropharyngeal cancer: an 18-year Danish population-based study with 2 169 patients[J]. Eur J Cancer, 2020, 134: 52-59.
[3] Mahal BA, Catalano PJ, Haddad RI, et al.Incidence and demographic burden of HPV-associated oropharyngeal head and neck cancers in the United States[J]. Cancer Epidemiol Biomarkers Prev, 2019, 28(10): 1660-1667.
[4] Carlander AF, Jakobsen KK, Bendtsen SK, et al.A contemporary systematic review on repartition of HPV-positivity in oropharyngeal cancer worldwide[J]. Viruses, 2021, 13(7): 1326.
[5] Xu T, Shen C, Wei Y, et al.Human papillomavirus(HPV) in Chinese oropharyngeal squamous cell carcinoma(OPSCC): a strong predilection for the tonsil[J]. Cancer Med, 2020, 9(18): 6556-6564.
[6] Wuerdemann N, Wittekindt C, Sharma SJ, et al.Risk factors for overall survival outcome in surgically treated human papillomavirus-negative and positive patients with oropharyngeal cancer[J]. Oncol Res Treat, 2017, 40(6): 320-327.
[7] Ang KK, Harris J, Wheeler R, et al.Human papillomavirus and survival of patients with oropharyngeal cancer[J]. N Engl J Med, 2010, 363(1): 24-35.
[8] Johnson DE, Burtness B, Leemans CR, et al.Head and neck squamous cell carcinoma[J]. Nat Rev Dis Primers, 2020, 6(1): 92-111.
[9] Kobayashi K, Hisamatsu K, Suzui N, et al.A review of HPV-related head and neck cancer[J]. J Clin Med, 2018, 7(9): 241.
[10] Parte S, Kaur AB, Nimmakayala RK, et al. Cancer-associated fibroblast induces acinar-to-ductal cell transdifferentiation and pancreatic cancer initiation via LAMA5/ITGA4 axis[J]. Gastroenterology, 2024, 166(5): 842-858.e5.
[11] Yang D, Liu J, Qian H, et al.Cancer-associated fibroblasts: from basic science to anticancer therapy[J]. Exp Mol Med, 2023, 55(7): 1322-1332.
[12] Chhabra Y, Weeraratna AT.Fibroblasts in cancer: unity in heterogeneity[J]. Cell, 2023, 186(8): 1580-1609.
[13] Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas[J]. Nature, 2015, 517(7536): 576-582.
[14] Leemans CR, Snijders PJF, Brakenhoff RH.The molecular landscape of head and neck cancer[J]. Nat Rev Cancer, 2018, 18(5): 269-282.
[15] Sasa N, Kishikawa T, Mori M, et al.Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer[J]. Nat Commun, 2025, 16(1): 1052.
[16] Cha J, Kim DH, Kim G, et al.Single-cell analysis reveals cellular and molecular factors counteracting HPV-positive oropharyngeal cancer immunotherapy outcomes[J]. J Immunother Cancer, 2024, 12(6): e008667.
[17] Kürten CHL, Kulkarni A, Cillo AR, et al.Investigating immune and non-immune cell interactions in head and neck tumors by single-cell RNA sequencing[J]. Nat Commun, 2021, 12(1): 7338-7354.
[18] Cillo AR, Kürten CHL, Tabib T, et al. Immune landscape of viral- and carcinogen-driven head and neck cancer[J]. Immunity, 2020, 52(1): 183-199.e9.
[19] Lim YX, Mierzwa ML, Sartor MA, et al.Clinical, morphologic and molecular heterogeneity of HPV-associated oropharyngeal cancer[J]. Oncogene, 2023, 42(40): 2939-2955.
[20] Cerami E, Gao J, Dogrusoz U, et al.The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data[J]. Cancer Discov, 2012, 2(5): 401-404.
[21] Gao J, Aksoy BA, Dogrusoz U, et al.Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal[J]. Sci Signal, 2013, 6(269): pl1.
[22] de Bruijn I, Kundra R, Mastrogiacomo B, et al. Analysis and visualization of longitudinal genomic and clinical data from the AACR project GENIE biopharma collaborative in cBioPortal[J]. Cancer Res, 2023, 83(23): 3861-3867.
[23] Tang Z, Kang B, Li C, et al.GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis[J]. Nucleic Acids Res, 2019, 47(W1): W556-w560.
[24] Sherman BT, Hao M, Qiu J, et al.DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021-update)[J]. Nucleic Acids Res, 2022, 50(W1): W216-w221.
[25] Newman AM, Steen CB, Liu CL, et al.Determining cell type abundance and expression from bulk tissues with digital cytometry[J]. Nat Biotechnol, 2019, 37(7): 773-782.
[26] Straub E, Dreer M, Fertey J, et al.The viral E8^E2C repressor limits productive replication of human papillomavirus 16[J]. J Virol, 2014, 88(2): 937-947.
[27] Yeo-Teh NSL, Ito Y, Jha S.High-risk human papillomaviral oncogenes E6 and E7 target key cellular pathways to achieve oncogenesis[J]. Int J Mol Sci, 2018, 19(6): 1706.
[28] Bedard MC, Chihanga T, Carlile A, et al.Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer[J]. Nat Commun, 2023, 14(1): 1975.
[29] Hu C, Zhang Y, Wu C, et al.Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma: opportunities and challenges[J]. Cell Death Discov, 2023, 9(1): 124.