Oral Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors: Salivary Gland Dysfunction and Mucosal Diseases

SIMPLE SUMMARY: The antitumor effect of immune checkpoint inhibitors (ICIs) such as antibodies against CTLA-4, PD-1, and PD-L1 is higher than that of conventional chemotherapy and is durable, improving the survival of patients with advanced head and neck squamous cell carcinoma (HNSCC). However, this therapy reduces the immune tolerance state and allows antitumor cytotoxic CD8(+) T cells to attack normal cells expressing self-antigens that cross-react with tumor antigens, and so it can induce immune-related adverse events (irAEs). Treatment of various malignancies, including HNSCC, with ICIs may result in the appearance of oral irAEs. In the oral cavity, irAEs such as Sicca syndrome, oral lichenoid reaction (OLR), and pemphigoid occur. It is necessary to elucidate the pathogenic mechanisms of these intractable diseases. Early diagnosis and appropriate approaches to irAE are needed for efficient treatment of advanced HNSCC by ICIs. ABSTRACT: Conventional chemotherapy and targeted therapies have limited efficacy against advanced head and neck squamous cell carcinoma (HNSCC). The immune checkpoint inhibitors (ICIs) such as antibodies against CTLA-4, PD-1, and PD-L1 interrupt the co-inhibitory pathway of T cells and enhance the ability of CD8(+) T cells to destroy tumors. Even in advanced HNSCC patients with recurrent diseases and distant metastasis, ICI therapy shows efficiency and become an effective alternative to conventional chemotherapy. However, as this therapy releases the immune tolerance state, cytotoxic CD8(+) T cells can also attack organs and tissues expressing self-antigens that cross-react with tumor antigens and induce immune-related adverse events (irAEs). When patients with HNSCC are treated with ICIs, autoimmune diseases occur in multiple organs including the skin, digestive tract, endocrine system, liver, and respiratory tract. Treatment of various malignancies, including HNSCC, with ICIs may result in the appearance of oral irAEs. In the oral cavity, an oral lichenoid reaction (OLR) and pemphigoid develop. Sicca syndrome also occurs in association with ICIs, affecting the salivary glands to induce xerostomia. It is necessary to elucidate the pathogenic mechanisms of these intractable diseases that are not seen with conventional therapy. Early diagnosis and appropriate approaches to irAEs are needed for efficient treatment of advanced HNSCC by ICIs.