Masen Ragsdale

Introduction. In recent years, there has been a rise in the incidences of human papilloma virus-positive oropharyngeal cancer, especially in men.^1,2 A persistent HPV 16 infection is responsible for 70% or more of oropharyngeal squamous cell carcinomas (OPSCC).^1,2 Risk factors for developing this type of cancer include risky sexual behavior and engaging in oral sex with multiple partners.¹ HPV is a double-stranded DNA virus that infects cutaneous and mucosal epithelium through direct contact with micro-abrasions.^1,2,3 HPV 16 has two oncoproteins, E6 and E7, that lead to cancer progression by degrading the p53 and pRb pathways.^2,3 These pathways are responsible for preventing unchecked DNA replication, DNA damage, and cell proliferation.³ The diagnosis of HPV+ OPSCC is difficult as it can have a benign clinical presentation leading to a late-stage diagnosis.¹ The current treatment for this cancer is surgical removal followed by radiation and chemotherapy. However, there is a great need for more targeted therapies as this treatment regimen and cancer can be quite disfiguring for the patient.^1,2 Methods and Results. Whole-genome sequencing and RNA seq data of both HPV- and HPV+ OPSCC cell lines identified distinctly different secondary mutations between the HPV- and HPV+ samples.⁵ The HPV+ cancer cell lines had secondary somatic mutations in genes PIK3CA, TRAF, DDX3X, CYLD, and EP300, genes already targeted by E6 and E7.⁵ Additionally, using whole-genome sequencing and RNAseq data showed HPV viral genome integration into the host genome causing gene breakpoints.⁶ Viral genome integration leads to genomic instability by disrupting genes involved in innate immune response such as CD274, an immune checkpoint, and the gene coding the programmed cell death ligand.⁶ Viral integration promotes overexpression of surrounding genes, many of which are cancer-promoting.⁶ Mutant cell lines with early stop codons in oncoproteins E6 and E7, showed increased expression of cGAS-STING proteins and increased interferon production.^7,8  HPV oncoproteins, E6 and E7, and secondary somatic mutations disrupt the cGAS-STING pathway which is responsible for detecting foreign viral DNA in the cell.^5,8 Disruption of the cGAS-STING pathway leads to host immune evasion and downregulation of interferon production.⁸ Mice injected with HPV+ squamous cell carcinoma cell lines in the flank and the tongue were treated with anti-PD-1 and STING agonist therapy.⁹ The combination immunotherapy of anti-PD-1 and a STING agonist led to increased CD 8+ T-cells and tumor regression in both the flank and tongue.⁹ Conclusions. Secondary somatic mutations and viral genome integration contribute to genomic instability by disrupting genes functioning in innate immunity, interferon signaling, apoptosis, cGAS-STING pathway, and DNA damage repair.^6,7 Additionally, HPV downregulates host immune response by targeting the cGAS-STING pathway and downregulating interferon production leading to immune evasion. The combination of genomic instability and immune evasion leads to carcinogenesis. Targeting these HPV mechanisms with an anti-PD-1 and STING agonist immunotherapy appears to be a promising therapy for HPV+ OPSCC cancer patients.

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