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. 2021 Jun 10:12:649863.
doi: 10.3389/fendo.2021.649863. eCollection 2021.

Immune Checkpoint Inhibitors-Related Thyroid Dysfunction: Epidemiology, Clinical Presentation, Possible Pathogenesis, and Management

Ling Zhan  1 , Hong-Fang Feng  1   2 , Han-Qing Liu  1 , Lian-Tao Guo  1 , Chuang Chen  1 , Xiao-Li Yao  1 , Sheng-Rong Sun  1
Affiliations

Immune Checkpoint Inhibitors-Related Thyroid Dysfunction: Epidemiology, Clinical Presentation, Possible Pathogenesis, and Management

Ling Zhan et al. Front Endocrinol (Lausanne). .

Abstract

Immune checkpoint inhibitors (ICIs) are a group of drugs employed in the treatment of various types of malignant tumors and improve the therapeutic effect. ICIs blocks negative co-stimulatory molecules, such as programmed cell death gene-1 (PD-1) and its ligand (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), reactivating the recognition and killing effect of the immune system on tumors. However, the reactivation of the immune system can also lead to the death of normal organs, tissues, and cells, eventually leading to immune-related adverse events (IRAEs). IRAEs involve various organs and tissues and also cause thyroid dysfunction. This article reviews the epidemiology, clinical manifestations, possible pathogenesis, and management of ICIs-related thyroid dysfunction.

Keywords: clinical manifestations; epidemiology; immune checkpoint inhibitors; immune-related adverse events; management; pathogenesis; thyroid dysfunction.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Thyroid dysfunction. FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid-stimulating hormone; TPO-Ab, thyroperoxidase antibodies; TG-Ab, thyroglobulin antibody; TRAb, TSH receptor antibodies; HT, Hashimoto’s thyroiditis; GD, Graves’ disease.
Figure 2
Figure 2
The proposed mechanism of immune checkpoint inhibitors-related thyroid dysfunction. Thyroid IRAEs may involve T and B-lymphocytes, multiply cytokines, and diverse factors. Immune checkpoints are activated to escape the immune killing and clearance effect in most malignant tumor cells. Some immunotherapeutic agents can eliminate the inhibitory effect of T cells, which restore the anti-tumor response. However, activation of the immune system can also affect normal organ tissues, and lead to cell death, eventually leading to organ IRAEs. Thyroid IRAEs present mainly as hypothyroidism, hyperthyroidism, and transient thyroiditis, seem to overlap with AITDs. HT and GD are AITDs that cause hypothyroidism and hyperthyroidism, respectively. HT is caused by impaired immune tolerance of autoantigens, the destruction of thyroid cells. The pathogenesis of HT is considered to be a complex autoimmune process involving various activate and infiltrate T lymphocytes, B lymphocytes, and various cytokines. Then a cellular immune response and humoral immune response are induced, leading to direct thyroid injury and further thyroid antigen exposure. The main pathogenesis of GD can be understood as the combination of TSH receptor and TR-Ab secreted and released by Th2 cell-dependent B cells. Immune checkpoints are proposed to play a role in inhibiting the autoimmune process by inhibiting various immune cells. Whether thyroid IRAEs have the same mechanism as AITDs, warrants further elucidation. PD-1, programmed cell death gene-1; PD-L1, programmed cell death gene-1 ligand; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; MHC, major histocompatibility complex; Th cells, helper T cells; CTL, cytotoxic T lymphocyte cell; Treg, T-regulatory cells; APCs, antigen-presenting cells; TSH, thyroid-stimulating hormone; TPO-Ab, thyroperoxidase antibodies; TG-Ab, thyroglobulin antibody; TRAb, TSH receptor antibodies; AITDs, autoimmune thyroid diseases; HT, Hashimoto’s thyroiditis; GD, Graves’ disease.
Figure 3
Figure 3
The hypothalamus-pituitary-thyroid/adrenal gland/ovary/testis axis. ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid-stimulating hormone; TRH, thyrotropin-releasing hormone.
Figure 4
Figure 4
Management flow chart for Immune checkpoint inhibitors-related thyroid dysfunction. FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone.
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