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

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.

The Continuum of Thyroid Disorders Related to Immune Checkpoint Inhibitors: Still Many Pending Queries

“…The path forward for the illumination of the pathogenesis of ir thyroid disorders could be an integrative framework of the association of ICPi with ir thyroid disorders, suggested very recently by the inspiring systematic review of Zhan et al The authors gathered all available data on the biological background discussed earlier in Section 3 of the present review, entitled “The biological background of ir thyroid disorders”, to conceptualize the framework of the association of the ICPi-induced immune response with the development of ir thyroid disorders. This framework was suggested to integrate T-cell-mediated immune responses, B-cell-mediated immune responses, specific cytokines, and genetic susceptibility [ 127 ].…”

“…Ir Graves’ disease has been suggested as the initial autoimmune ir thyroid disorder, which triggers the exposure of thyroid cell antigens to immune cells, which, in turn, results in the development of ir autoimmune hypothyroidism due to the predominance of Th1 cells. Additionally, anti-PD-1 mAbs may stimulate thyroid autoimmunity via counteraction of the inhibitory effect of Treg on autoimmunity, given that PD-1 is critical for the proliferation and differentiation of Treg [ 127 ].…”

“…Both the negativity or positivity of thyroid autoantibodies has been described in the setting of ir thyroid disorders, while it has also been speculated that thyroid autoantibodies can be the result of humoral immune response triggered by the release of thyroid antigens in the context of destructive thyroiditis. Whether patients with previous subclinical autoimmune thyroid diseases are at an increased risk for ir thyroid disorders has yet to be clarified [ 127 ].…”

“…A suggested mechanism through which ICPi may confer a genetic susceptibility to thyroid autoimmunity is the upregulation of HLA-DR expression, as described in the setting of pembrolizumab-induced thyroiditis [ 127 ].…”

“…A speculative mechanism underlying anti-PD-1 mAbs-induced ir thyroid disorders is the polarization of the immune response towards a predominant Th1 profile, known to foster the genesis of organ-specific autoimmune diseases, including Hashimoto’s thyroiditis. This polarization is indicated by the integration of increased levels of proinflammatory Th1 cytokines (IFN-γ and IL-2), produced by an increased number of CD4 + Th1 cells with decreased Th2 cytokine activity [ 127 ].…”