From biomarkers to therapeutic targets: the promise of PD-L1 in thyroid autoimmunity and cancer

Abstract

The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint proteins hold promise as diagnostic, prognostic, and therapeutic targets for precision oncology. By restoring antitumor T cell surveillance, the high degree of effectiveness of the immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment. However, the majority of patients (65-80 %) treated with ICIs experience significant side effects, called immune-related adverse events (irAEs), resulting in autoimmune damage to various organs. Therefore, broadening the clinical applicability of these treatments to all cancer types requires an improved understanding of the mechanisms linking cancer immune evasion and autoimmunity. The thyroid is the endocrine gland the most frequently involved in autoimmunity and cancer, the growing incidence of which is raising serious public health issues worldwide. In addition, the risk of developing thyroid cancer is increased in patients with autoimmune thyroid disease and thyroid dysfunction is one of the most common irAEs, especially with PD‑1/PD-L1 blockade. Therefore, we chose the thyroid as a model for the study of the link between autoimmunity, irAEs, and cancer. We provide an update into the current knowledge of the PD‑1/PD-L1 axis and discuss the growing interest of this axis in the diagnosis, prognosis, and management of thyroid diseases within the context of autoimmunity and cancer, while embracing personalized medicine.

Keywords: PD-1/PD-L1; Thyroid autoimmunity; biomarker; immune checkpoint inhibitors; thyroid cancer.

Figure 1

Role of the PD-1/PD-L1 pathway in thyroid pathogenesis. Upper panel graphical displays the thyroid immune microenvironment in AITD (Graves' disease and Hashimoto's thyroiditis, A), thyroid immune-related adverse events (B), and thyroid cancer (C). Lower panel. At the molecular level, the highly activated lymphocytes, which are characterized by the expression of PD-1 and IFNγ, are in close contact with thyrocytes and thyroid tumor cells. Either IFNγ or/and BRAF^V600E induce the expression of PD-L1 by the epithelial cells, which binds to its receptor PD-1 on lymphocytes and thereby restrains autoimmune attacks in AITD (D) and promotes thyroid tumor immune tolerance (F). Note that both AITD and TC release the serum-soluble form of PD-L1, which may contribute with the tissue PD-L1 to the immune escape and be considered as biomarkers and therapeutic targets (sPD-L1, E). Abbreviations: AITD, Autoimmune thyroid disease; Anti-TSH-R-ab, Anti-receptor of the thyroid-stimulating hormone antibody; Anti-TPO-ab, Anti-thyroid peroxidase antibody; Auto‑ab, Auto-antibodies; CLT, Chronic lymphocytic thyroiditis; GD, Grave's disease; IFNγ, Interferon-gamma; irAEs, Immune-related adverse events; PD-1, Programmed-cell death receptor 1; PD-L1, Programmed-cell death ligand 1; SNP, Single nucleotide polymorphism.

Figure 2

Promise of PD-L1 in the diagnostic, prognostic, and management of thyroid diseases. Comparison of some clinical characteristics, and treatment options, of patients with AITD, irAE, and TC emphasizing the percentage of positive cases for PD-L1, the interest of PD-L1 as a diagnosis and prognostic biomarkers as well as the promises of clinical trials using anti-PD‑1 and anti-PD-L1 drugs (see for details the tables 1-5). Abbreviations: 18FDG, 18 fluorodeoxyglucose; AITD, Autoimmune thyroid disease; Anti-TSH-R-ab, Anti-receptor of the thyroid-stimulating hormone antibody; Anti-TPO-ab, Anti-thyroid peroxidase antibody; ATA, American thyroid association; BRAFi, BRAF inhibitor; CLT, Chronic lymphocytic thyroiditis; EFVPTC, Encapsulated follicular variant of papillary thyroid carcinoma; GD, Grave's disease; HT, Hashimoto's thyroiditis; ICIs, Immune checkpoint inhibitors; IFNγ, Interferon-gamma; irAEs, Immune-related adverse events; NIFTP, Non-invasive follicular thyroid neoplasm with papillary-like nuclear features; OS, Overall survival; Parafollicular C, Parafollicular carcinoma; PD-1, Programmed-cell death receptor 1; PD-L1, Programmed-cell death ligand 1; PTC, Papillary thyroid carcinoma; RAI, Radioiodine therapy; SNP, Single nucleotide polymorphism; TC, Thyroid carcinoma; TILs, Tumor-infiltrating lymphocytes; PD-1, Programmed-cell death receptor 1; PD-L1, Programmed-cell death ligand 1; PFS, Progression-free survival; SNP, Single-nucleotide polymorphism; TMB, Tumor mutational burden; WDTC, Well-differentiated thyroid carcinoma.