Thyroid dysfunction (TD) induced by PD-1/PD-L1 inhibitors in advanced lung cancer

Abstract

Background: Thyroid Dysfunction (TD) is a common immune-related adverse events (irAEs) in the treatment of advanced lung cancer with programmed cell death protein 1 (PD-1) and programmed death 1 ligand (PD-L1) inhibitors, with incidence accounting for 6-8% of all irAEs. The incidence of TD is receiving increasing attention from clinicians, given its potential impact on clinical efficacy. However, the molecular mechanisms, biomarkers, and clinical impact of TD resulting from PD-1/PD-L1 inhibitor treatment in advanced lung cancer are unclear.

Objective: To present a comprehensive review of current advancements in research about the molecular mechanisms, influential factors, and clinical manifestations in the treatment of advanced lung cancer with PD-1 and PD-L1 inhibitors, as well as the correlation between TD and the efficacy of PD-1 and PD-L1 inhibitors.

Methods: A systematic search was conducted using PubMed, Web of Science, Cochrane Library, Embase and Google Scholar databases, with the keywords including thyroid dysfunction, efficacy, mechanisms, immune checkpoint inhibitors, PD-1/PD-L1 inhibitors, and advanced lung cancer.

Results: PD-1/PD-L1 inhibitors can induce T cell-mediated destructive thyroiditis, thyroid autoantibody-mediated autoimmunity, and a decrease in the number of immunosuppressive monocytes (circulating cluster of differentiation (CD)14⁺ human leukocyte antigen (HLA)-DRlow/negatives monocytes, CD14⁺ HLA-DR ^{+ lo/neg}), leading to TD. Several factors, including peripheral blood inflammatory markers, body mass index (BMI), baseline thyroid-stimulating hormone (TSH) level, gender, smoking history, hypertension, and previous opioid use, may also contribute to the development of TD. However, there is currently a lack of reliable predictive biomarkers for TD, although anti-thyroid antibodies, TSH levels, and peripheral blood inflammatory markers are expected to be predictive.Interestingly, some studies suggested a positive correlation between TD and clinical efficacy, i.e., patients experiencing TD showed better outcomes in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), compared with those without TD. However, most of these studies were single-center and had small sample sizes, so more multi-center studies are needed to provide further data support.

Conclusion: TD resulting from PD-1/PD-L1 inhibitor treatment in advanced lung cancer may be associated with good clinical outcomes. The clarification of the molecular mechanisms underlying TD and the identification of reliable predictive biomarkers will guide clinicians in managing TD in this patient population.

Keywords: Advanced lung cancer; Efficacy; Immune checkpoint inhibitors; PD-1/PD-L1 inhibitors; Thyroid dysfunction.

Fig. 1

Molecular mechanisms and influencing factors of thyroid dysfunction (TD).

Fig. 2

Molecular mechanisms for the occurrence of TD induced by PD-1/PD-L1 inhibitors in the treatment of advanced lung cancer (adapted from Refs. [[17], [18], [19], [20], [21],28,30,40]).

Fig. 3

(A) Under normal circumstances, the combination of PD-1 and PD-L1 inhibits further activation of T cells, induces apoptosis of activated T cells, and produces large amounts of IL-10, further promoting immunosuppression as a means of maintaining self-tolerance and preventing autoimmunity (adapted from Ref. [81]). (B) PD-L1 expression on the surface of tumor cells is significantly upregulated by the combination of specific tumor microenvironment, various cytokines (IFN-γ) and chemokines, which can be used to achieve immune escape and thus reduce the anti-tumor immune response (adapted from Ref. [82]).

Fig. 4

PD-1 and PD-L1 inhibitors work by binding PD-1 and PD-L1 respectively, blocking the binding pathway between PD-1 and PD-L1 and reactivating the T cells for anti-tumor effects (adapted from Ref. [83]).