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

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.

Keywords: Sicca syndrome; cellular and humoral tumor immunity; head and neck squamous cell carcinoma; immune checkpoint inhibitor; immune-related adverse event; oral cavity; oral lichenoid reaction; pemphigoid.

Figure 1

CTLA-4 and PD-1/PD-L1 in cellular (A) and humoral (B) tumor immunity. (A) In the CD8⁺ T cell-based pathway, when tumor antigens are released into the tumor microenvironment from dying tumor cells, DCs take up the protein antigens and decomposes them to peptide antigens. In regional lymph nodes, the peptide antigens are cross-presented via MHC class I on the cell surface and recognized by the TCR of CD8⁺ T cells. In addition, the co-stimulatory binding of CD80/86 of DCs with CD28 of T cells is required for naïve CD8⁺ T cells to differentiate into cytotoxic CD8⁺ T cells. Activated CD8⁺ T cells express the co-inhibitory molecule CTLA-4 to prevent excess activation of CD8⁺ T cells. CD8⁺ T cells move to a peripheral tumor site and recognize tumor peptide antigens presented via MHC class I and exert antitumor activity. However, PD-I on CD8⁺ T cells binds PD-L1 on tumor cells and suppresses the activity of CD8⁺ T cells. Treg cells locally suppress the activity of CD8⁺ T cells and CD4⁺ helper cells. (B) The germinal center (GC) plays an important role in the proliferation and differentiation of B cells. Tfh cells physically bind to GC B cells by co-stimulatory/co-inhibitory pairs such as CD28–CD80/86, CD40L–CD40, ICOS–ICOSL, PD-1, and PD-L1. BCR expressed on B cells detects the protein antigens, and take them into the cells. Peptide antigens processed in B cells are then presented via MHC class II and recognized by Tfh cells. Interaction between Tfh and B cells promotes the differentiation of GC B cells into plasma cells and memory B cells. Tfr cells suppress Tfh and B cells. LN, lymph node; Treg, regulatory T; TCR, T cell receptor; irAEs, immune-related adverse events; GC, germinal center; Tfh, T follicular helper; Tfr, T follicular regulatory; PC, plasma cell; BCR, B cell receptor.

Figure 2

Characteristics of 76 previously reported patients with ICI-induced Sicca syndrome. (A) Sex. (B) Types of underlying malignancies. (C) Time to onset, months. (D) Prevalence of Sicca syndrome-related serum autoantibodies. (E) Other irAEs. (F) Degree of improvement of irAEs.