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Review
. 2021 Oct 21;13(21):5277.
doi: 10.3390/cancers13215277.

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

Maria V Deligiorgi  1 , Sofia Sagredou  1 , Lampros Vakkas  1 , Dimitrios T Trafalis  1
Affiliations
Review

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

Maria V Deligiorgi et al. Cancers (Basel). .

Abstract

Background: Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors.

Methods: The present review provides a comprehensive and updated overview of the thyroid disorders related to ICPi, namely to inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death (PD) 1 (PD-1), and the ligand of the latter (PD-L1).

Results: With the increasing recognition of ir thyroid disorders, many outstanding issues have emerged. Ir thyroid disorders are reminiscent of, but not identical to, thyroid autoimmunity. Interclass and intraclass ICPi differences regarding thyroid immunotoxicity await interpretation. The available data concerning the predictive value of thyroid autoantibodies for the development of ir thyroid disorders are inconclusive. Mounting data indicate an association of ir thyroid disorders with ICPi efficacy, but a causative link is still lacking. The path forward is a tailored approach, entailing: (i) the validation of tumor-specific, patient-specific, and ICPi-specific predictive factors; (ii) appropriate patient selection; (iii) the uncoupling of antitumor immunity from immunotoxicity; (iv) a multidisciplinary initiative; and (v) global registry strategies.

Conclusions: Untangling and harnessing the interrelationship of immuno-oncology with endocrinology underlying the ir thyroid disorders will yield the optimal patient care.

Keywords: Graves’ disease; anti-CTLA-4 monoclonal antibodies; anti-PD-1 monoclonal antibodies; anti-PD-L1; hyperthyroidism; hypothyroidism; immune checkpoint inhibitors; immune-related adverse events; monoclonal antibodies; thyroid autoantibodies; thyrotoxicosis.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
The hypothalamus–pituitary–thyroid (H–P–T) axis and the main actions of thyroid hormones (TH). The TH levels are regulated by the hypothalamic–pituitary–thyroid (HPT) axis. Thyrotropin-releasing hormone (TRH) is synthesized and released by hypothalamus (H) and stimulates the pituitary (P) gland to synthesize and secrete a thyroid-stimulating hormone (TSH), which, in turn, stimulates the thyroid (T) to synthesize and release TH. TH inhibit TRH and TSH synthesis and release through negative feedback mechanisms. TH actions affect multiple organs and tissues and physiological functions. The TH effects on the heart, liver, and adipose tissue are both direct and indirect through increased function of the sympathetic nervous system. Abbreviations: chol, cholesterol; GIS, gastrointestinal system; Glu, glucose; H, hypothalamus; P, pituitary; T, thyroid; TH; thyroid hormones; TRH, thyrotropin releasing hormone; TSH, thyroid-stimulating hormone.
Figure 2
Figure 2
Suggested mechanisms of the biological background of ir thyroid disorders. Abbreviations: CD, cluster of differentiation; CLI, chronic lymphocytic infiltration; FC, follicular cells; HLA, human leukocyte antigen; NK, natural killers; PD-1, programmed cell death protein 1; Tfh, follicular T-helper cells.
Figure 3
Figure 3
A comprehensive approach to ir thyroid disorders. * HDG are recommended for certain cases of grades 3 and 4 destructive thyroiditis. Abbreviations: ATA, antithyroid antibodies; ATD, antithyroid drugs; b-blockers; beta-blockers; DT, destructive thyroiditis; fT4, free T4; FU, follow-up; G, grade; GCs, glucocorticoids; HC, hydrocortisone; HDG, high-dose glucocorticoids; NTIS, nonthyroidal illness syndrome; TFT, thyroid function tests; THR, thyroid hormone replacement; TSH, thyroid-stimulating hormone; RAI, radioiodine; TT, total thyroidectomy; Tx, treatment.
Figure 4
Figure 4
Future perspectives concerning ir thyroid disorders. The quarters of the inner circle depict the main future perspectives in the management of ir TD, and the corresponding rectangles depict the relevant initiatives. The final goal is to ensure optimal ICPi efficacy and safety. Abbreviations: ATA, antithyroid antibodies; ICPi, immune checkpoint inhibitors; TD, thyroid disorders.
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