Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights Into Underlying Involved Mechanisms

Abstract

Context: Thyroid immune-related adverse events (irAEs) in patients treated with programmed death receptor-1 (PD-1) blockade are increasingly recognized as one of the most common adverse effects. Our aim was to determine the incidence and examine the potential mechanisms of anti-PD-1-induced thyroid irAEs.

Design: Single-center, retrospective cohort study.

Patients and measurements: We studied 93 patients with advanced cancer (ages 24 to 82 years; 60% males) who received at least one infusion of pembrolizumab. Thyroid test results and thyroid imaging modalities were reviewed. Comprehensive 10-color flow cytometry of peripheral blood was performed.

Results: Thirteen (14%) thyroid irAEs were observed. Thyroiditis occurred in seven patients (54%), from which four recovered. New onset of hypothyroidism overt/subclinical developed in three patients. Levothyroxine dosing required doubling in three patients with a known history of hypothyroidism. Thyroperoxidase antibodies were positive in the minority of the patients [4/13 (31%)] and diffuse increased 18fludeoxyglucose uptake of the thyroid gland was observed in the majority [7/11 (64%)] of patients. We observed more circulating CD56+CD16+ natural killer (NK) cells and an elevated HLA-DR surface expression in the inflammatory intermediate CD14+CD16+ monocytes in anti-PD-1-treated patients.

Conclusions: Thyroid dysfunction is common in cancer patients treated with pembrolizumab. Reversible destructive thyroiditis and overt hypothyroidism are the most common clinical presentations. The mechanism of thyroid destruction appears independent of thyroid autoantibodies and may include T cell, NK cell, and/or monocyte-mediated pathways. Because the thyroid is a frequent target of anti-PD-1 therapies, patients with therapeutically refractory thyroid cancer may be ideal candidates for this treatment.

Figure 1.

Overview of the investigated cohort of pembrolizumab-treated cancer patients. Q, every.

Figure 2.

Immunophenotypic differences in patients with autoimmune thyroiditis compared with patients with pembrolizumab-induced thyroiditis. Immune cell populations were measured by flow cytometry as cell counts (cells/µL), % of a parent population, or mean fluorescence intensity (MFI) where indicated. Healthy volunteers (HV; circles), patients with autoimmune thyroiditis (AutoImm; squares), and patients with pembrolizumab-induced thyroiditis (α-PD-1; triangles) are shown. The horizontal line represents the mean value for each cohort. *P < 0.05; **P < 0.001.

Figure 3.

Comparisons of PD-1 expression on peripheral blood T cells from healthy volunteer controls, patients with autoimmune thyroiditis, and patients with pembrolizumab-induced thyroiditis. (a) Flow cytometric dot plots outlining the gating strategy for measuring PD-1 expression. CD4⁺ and CD8⁺ T cells were displayed from a CD3⁺ parent T-cell gate (not shown). PD-1 expression is displayed from both CD4⁺ and CD8⁺ T cells. Gates depicting PD-1–positive cells were set using fluorescence minus one staining protocols where PD-1 fluorescent antibody was removed. Representative dot plots from a patient with autoimmune thyroiditis and a patient with pembrolizumab-induced thyroiditis are shown. (b) PD-1 expression of the three cohorts: HV (circles), AutoImm (squares), and α-PD-1 (triangles). The horizontal line represents the mean value for each cohort. **P < 0.001.