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Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitors in NSCLC: Insights From
Xiaoyu Li1, Qin Xiang2, Yijia Gong3
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
Purpose:
Thyroid immune-related adverse events (irAEs) are common with immune checkpoint inhibitor (ICI) therapy in nonsmall cell lung cancer (NSCLC), but their drug-specific risks, clinical characteristics, and immune features remain incompletely understood. This study aimed to systematically characterize thyroid irAEs, identify relevant clinical factors, and explore preliminary immune features associated with thyroid irAEs.
Methods:
We integrated FDA Adverse Event Reporting System (FAERS) pharmacovigilance data, a single-center retrospective case-control analysis, and a publicly available peripheral blood single-cell RNA sequencing (scRNA-seq) dataset from ICI-treated NSCLC patients. Disproportionality analysis evaluated thyroid irAE signals across ICI classes and regimens. In the retrospective analysis, logistic regression assessed factors associated with thyroid irAE occurrence, initial clinical subtype, and progression from thyrotoxic phase to hypothyroidism. ScRNA-seq analysis explored preliminary immune features.
Findings:
Among 1022 FAERS thyroid irAE cases, anti-PD-1 monotherapy, particularly nivolumab, showed the strongest hypothyroidism signal, whereas nivolumab plus ipilimumab was most associated with hyperthyroidism. Rare but significant signals were also detected: thyrotoxic crisis with nivolumab plus ipilimumab (reporting odds ratio [ROR] = 20.11, n = 5) and pembrolizumab (ROR = 4.22, n = 4), Graves' disease with nivolumab plus ipilimumab (ROR = 9.05, n = 4), and exophthalmos with nivolumab (ROR = 11.87, n = 3). In the retrospective analysis, baseline TPOAb and/or TgAb positivity was the only factor associated with thyroid irAE occurrence (odds ratio = 10.55, 95% confidence interval: 4.57-28.89). Among patients with thyroid irAEs, TPOAb and/or TgAb positivity was associated with initial thyrotoxic phase presentation and earlier onset, whereas higher baseline TSH was associated with initial hypothyroidism presentation. Among patients with initial thyrotoxic phase, 58.9% progressed to hypothyroidism, with higher baseline TSH and BMI associated with progression. Exploratory scRNA-seq analysis suggested a shift from naive T cells toward cytotoxic effector CD8⁺ T cells, accompanied by activation of TCR signaling and ER-Golgi vesicle transport pathways.
Implications:
This study identifies drug-specific thyroid irAE signals, clinically relevant risk factors and preliminary immune features associated with thyroid irAEs. Baseline thyroid autoantibody status, TSH level, and BMI support risk-adapted thyroid monitoring and clinical management, while the overall findings provide a basis for further validation in larger cohorts and mechanistic studies.
Insights
Immune checkpoint inhibitor (ICI) therapy for non-small cell lung cancer can cause thyroid immune-related adverse events (irAEs). Baseline thyroid autoantibodies and TSH levels help predict risk and guide management of these events.
Area of Science:
- Oncology
- Immunology
- Endocrinology
Background:
- Immune checkpoint inhibitors (ICIs) are crucial in non-small cell lung cancer (NSCLC) treatment.
- Thyroid immune-related adverse events (irAEs) are common but not fully understood.
- Drug-specific risks and clinical features of thyroid irAEs require further characterization.
Purpose of the Study:
- To systematically characterize thyroid irAEs in NSCLC patients treated with ICIs.
- To identify clinical factors associated with thyroid irAE occurrence and progression.
- To explore preliminary immune features linked to thyroid irAEs.
Main Methods:
- Integrated pharmacovigilance data (FAERS), retrospective case-control analysis, and single-cell RNA sequencing (scRNA-seq).
- Disproportionality analysis to assess ICI drug-specific signals for thyroid irAEs.
- Logistic regression and scRNA-seq to analyze clinical factors and immune profiles.
Main Results:
- Anti-PD-1 monotherapy (nivolumab) showed strong hypothyroidism signals; nivolumab plus ipilimumab linked to hyperthyroidism.
- Baseline thyroid autoantibodies (TPOAb/TgAb) predicted irAE occurrence and initial thyrotoxic phase.
- Progression to hypothyroidism was associated with higher baseline TSH and BMI; scRNA-seq indicated T cell shifts.
Conclusions:
- Identified drug-specific thyroid irAE signals and key clinical risk factors.
- Baseline thyroid autoantibody status, TSH, and BMI inform risk-adapted monitoring and management.
- Findings provide a foundation for further validation and mechanistic studies in thyroid irAEs.
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