Impact of HPV Infection on the Immune System in Oropharyngeal and Non-Oropharyngeal Squamous Cell Carcinoma: A Systematic Review

Objectives: To review the current knowledge regarding the involvement of human papilloma virus (HPV) infection and the immune system in the development of head and neck squamous cell carcinoma (HNSCC). Methods: An electronic literature search was conducted to identify articles published between 1990 and 2019 pertaining to tumor-infiltrating immune cells (TICs) in HNSCC using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Issues of clinical relevance, including tumor location, the number of tumor samples, the inclusion of additional specimens (dysplastic or normal mucosa), tumor size, methods used for HPV detection, relationship between antigen expression and patient characteristics (age, gender, smoking, alcohol consumption, etc.), and prognostic data (overall survival (OS) and recurrence-free survival (RFS)) were assessed by four blinded investigators. Results: The search identified 335 relevant studies, of which 41 met the inclusion criteria. Of these, 7 studies focused on the peripheral blood immune cell concentration in patients with HNSCC according to HPV status, and 36 studies investigated TICs in the intraepithelial and/or stromal compartment(s) according to HPV status. The immune cells studied were CD8+ T cells (N = 19), CD4+ T cells (N = 7), regulatory T cells (Tregs, N = 15), macrophages (N = 13), myeloid-derived suppressor cells (MDSCs, N = 4), and Langerhans cells (LCs, N = 2). Conclusions: Irrespective of tumor location, CD8+ and CD4+ T cells appear to play a key role in the development of HPV−related HNSCC, and their infiltration is likely associated with a significant impact on OS and RFS. To date, the roles and prognostic value of Tregs, macrophages, DCs and MDSCs remain unclear.