Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma and the Immune System: Pathogenesis, Immunotherapy and Future Perspectives

Abstract

Oropharyngeal squamous cell carcinoma (OPSCC), a subset of head and neck squamous cell carcinoma (HNSCC), involves the palatine tonsils, soft palate, base of tongue, and uvula, with the ability to spread to adjacent subsites. Personalized treatment strategies for Human Papillomavirus-associated squamous cell carcinoma of the oropharynx (HPV⁺OPSCC) are yet to be established. In this article, we summarise our current understanding of the pathogenesis of HPV⁺OPSCC, the intrinsic role of the immune system, current ICI clinical trials, and the potential role of small molecule immunotherapy in HPV⁺OPSCC.

Keywords: cancer of the oropharynx; head & neck cancer; immune system; immunotherapy.

Figure 1

HPV Patho-oncogenesis. The HPV virion invades the epithelium of the oropharynx, infecting the basal layer of cells. Within these cells, E6 and E7 inhibit p53 (tumour protein 53) and pRb (retinoblastoma protein) respectively, affording the cell the ability to replicate without regulation by these Tumor Suppressor Genes (TSGs). Further to this E6, promotes carcinogenesis in several ways: firstly, through inhibition of pro-apoptotic proteins (namely, GADD34/PP1 (growth arrest and DNA damage induced transcript 34/serine/threonine protein phosphatase), Procaspase 8, FADD (FAS-associated death domain protein), or Bak) [85,86,87,88]; secondly, by suppressing host–IFN (interferon) antiviral response by downregulating IRF3 (interferon regulatory factor 3) and Tyk2 (Tyrosine kinase 2); thirdly, by disrupting tissue integrity through degradation of PDZ proteins (PDZ proteins play an important role in anchoring receptor proteins in the cell membrane to cytoskeletal components; these proteins also play an integral role in signal transduction complexes. Interaction with certain proteins promotes oncogenic potential) via expression of a PDZ protein binding motif (PSD-95/D1g/ZO-1) [89]; and finally, by promoting cellular immortalisation by targeting NFX1-91, which is an endogenously expressed transcriptional regulator of human telomerase reverse transcription (hTERT) (active in stem cells) that promotes telomerase induction and cellular immortalisation [90].

Figure 2

The different phases of the cancer immunoediting process. (A) Initiation of a carcinogenic process, producing cancer cells and development of a tumour. (B) Elimination is characterised by immunosurveillance leading to suppression of the transformed cancer cells directed by inflammatory and cellular cytotoxicity processes. (C) Equilibrium is characterised by a balance between the immune system and the tumour, leading to partial control of the tumour. This phase is characterised by high tumour mutational burden due to selective immune pressure. (D) Escape is caused by the increased selective pressure caused by the immune system leading the tumour to acquire immune evasion, resulting in uncontrolled tumour proliferation. Arrow indicates increasing Tumour heterogeneity and Immune selection. Figure adapted from “Cancer Immunoediting”, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates, accessed on 10 February 2024.

Figure 3

HPV’s immune evasion strategies. (A) HPV infects basal epithelial cells and utilises the progressive differentiation of keratinocytes to conceal its viral replication process from the immune system. Immune detection is prevented since the most viral gene expression happens in superficial epithelial layers and since no unexpected cell death or inflammation occurs. (B) HPV E6 and E7 oncogenes reduce secretion of chemokines, CCL20 and CXCL14, which hinders Langerhan’s and dendritic cell recruitment. (C) HPV E5 and E7 oncogenes prevent antigen presentation to cytotoxic T cells by downregulating major histocompatibility complex (MHC) class I expression. (D) HPV E5 and E7 oncogenes inhibit the cGAS-STING (cyclic GMP–AMP synthase, stimulator of interferon genes) pathway, which responds to aberrant DNA from viruses by activating the innate immune system. (E) HPV E5, E6, and E7 oncogenes can also inhibit IFN-stimulated gene expression (e.g., TLR3, RIG-I, MDA5, TRAIL, XAF1, IFIT1, MX1). cGAMP = 2′3′ cyclic GMP–AMP, CTL = cytotoxic T cell, DC = dendritic cell, IFN = Interferon, LC = Langerhan’s cell, MHC-I = major histocompatibility complex-I.