The Microenvironment of Head and Neck Cancers: Papillomavirus Involvement and Potential Impact of Immunomodulatory Treatments

Cancer progression can be understood as the result of deregulation of tumors' immune microenvironments. Recent studies of the alterations of microenvironments highlight their significant influence on the prognosis of patients with head and neck squamous cell carcinoma (HNSCC). It is necessary to better characterize tumor-infiltrating lymphocytes by focusing, in particular, on the tumor escape mechanisms from immune surveillance. One of the best described tumor immune system evasion mechanisms is the expression of co-stimulation molecules that constitute so-called "immune checkpoints". These molecules regulate the immune response by either activating or inhibiting its effects. The programmed cell death 1 (PD-1) surface protein is an inhibitory co-stimulation molecule that induces exhaustion of activated T-lymphocytes (TLs, T cells) through binding with its ligands, PD-L1 and PD-L2. Half of HNSCCs exhibit PD-L1 expression with higher expression identified in human papillomavirus (HPV) positive tumors. Numerous studies have shown differences between the microenvironments of HPV+ and HPV- cancers. Notably, infiltrations of exhausted CD4+ PD1+ and CD8+ PD1+ T cells are far higher in the microenvironment of HPV+ tumors. The FDA has approved the use of molecules that target PD-1 for the treatment of HNSCC. The first results of clinical trials with anti-PD-1 blockers in HNSCC show improved patient survival, particularly long-term survival without recurrence. However, discordant results were sometimes observed, and improvements in defining cellular predictive markers are necessary. With the development of immunotherapies, pathologists play a role in the selection of patients who are eligible for specific treatments and assessment of their prognosis in greater detail. An automated, quantitative in situ imaging system that integrates both multispectral imaging and automated slide scanning could be developed in pathology laboratories. The evaluation of PD-L1 expression has only been used to stratify the administration of first-line immunotherapy. The validation of these tests and their routine interpretation is essential. No specific recommendation is adopted for HPV+ HNSCC.