The Double-Edged Sword-How Human Papillomaviruses Interact With Immunity in Head and Neck Cancer

Abstract

Patients with human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) have remarkably better prognosis, which differs from HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) with respect to clinical, genomic, molecular, and immunological aspects, especially having the characteristics of high levels of immune cell infiltration and high degrees of immunosuppression. This review will summarize immune evasion mechanisms in HPV-positive HNSCC, analyze the host various immune responses to HPV and abundant numbers of infiltrating immune cell, and discuss the differences between HPV-positive HNSCC with cervical cancer. A deeper understanding of the immune landscape will help new concepts to emerge in immune-checkpoint oncology, which might be a valuable add-on to established concepts.

Keywords: head and neck squamous cell carcinoma (HNSCC); human papilloma virus (HPV); immune escape; immune responses; immunotherapy.

Figure 1

The mechanisms for HPV-related tumor cells to escape immune system. (A) Because of the down-regulation of TLR 7 and 9, DCs could not be activated. Thus, HPV could not be recognized by the immune system. (B) HPV E5, E6 and E7 cause the low expression of MHC class I and II via repressing MHC I-associated promoters, preventing the breakdown of invariant chain and inhibiting antigen processing machinery components, which lead to the failure of the process of antigen presentation. (C) HPV-related tumors cells express PD-L1 which interacts with PD-1 to let T cell exhausted. (D) HPV prevents IκB kinase activation, inhibits IκBα phosphorylation and interferes with NF-κB p65-dependent transcriptional activity to manipulate the NF-κB signaling and regulate inflammation responses. Then some immunosuppressive inflammatory mediators (e.g., IL-10 and TGF-β) are released. (E) HPV influences the number and activity of LCs via reducing the levels of E-cadherin and interfering with MIP-3 transcription.

Figure 2

Architecture of the tonsils and possible explanation for the immune responses of HPV-positive HNSCC. The palatine and lingual tonsils are the most common infection sites for HPV. The tonsils which are lined with stratified squamous epithelium are part of oropharyngeal lymphoid tissues and have several lymphoid follicles in the lamina propria. And the epithelium invaginates into the underlying tissue to form tonsillar crypts which are covered by reticulated epithelium. These crypts are able to greatly enlarge the tonsillar surface area, thereby dramatically improving the efficiency of antigen capture and immune surveillance. The reticulated epithelium that has an incomplete basal cell layer help to the presentation of antigens and the infiltration of immune cells and APC. Besides, the permissive nature serves to virus infection without the required microlesion in cervical cancer. And HPV-related HNSCC has a significantly increased infiltration of immune cells, especially CD8+ T cells in the tumor microenvironment, which could be partly due to the special characteristics of the crypts and reticulated epithelium.