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Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer
Open accessAbstract
Background Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.Patient and methods Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.Results Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04).Conclusions Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.
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“Two retrospective and two prospective studies reported that positive TPOAb and/or thyroglobulin autoantibodies (TgAb) are associated with a 40 to 70% risk of hypothyroidism during treatment”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
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“and that patients who had ICPi-induced hypothyroidism had positive anti-thyroid autoantibodies in 75 to 100% of cases [54,55,56,57].”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
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“Note that in the Osorio study [56], survival was better if patients developed ICPi-induced thyroid dysfunction”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
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“Osorio et al. observed that thyroid dysfunction in patients receiving anti-PD-1 therapy may be related to the presence of antithyroid antibodies [35].”
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Multiple or Single Endocrine Abnormalities Associated With Immune Checkpoint Inhibitors
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“Thyroid dysfunction during PD-1 inhibitor treatment correlates with improved responses and can be used as a predictive factor for improved treatment outcomes (19).”
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“The incidence of thyroid dysfunction in this cohort is higher than that in reports from larger anti-PD-1 clinical trials, where rates range from 5% to 30% (13, 14, 15).”
ResultThe role of PET/CT in thyroid autoimmune diseases
CALIFARETTI, E., Dall’Armellina, S., Rovera, G., Finessi, M., & Deandreis, D. (2022) · The Quarterly Journal of Nuclear Medicine and Molecular Imaging · doi:10.23736/s1824-4785.22.03464-1 · Cited by 5
A Rare Case of Pembrolizumab-Associated Graves’ Disease
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“For instance, in a study conducted by Osorio and colleagues, anti-thyroid antibodies were present in eight out of 10 patients who developed thyroid dysfunction during pembrolizumab therapy [16].”
BackgroundPach, J., & Leventhal, J. S. (2022) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.2023046895 · Cited by 5
The interplay between the microbiome and colonic immune system in checkpoint inhibitor therapy
Dehinsilu, J., Sergaki, C., Amos, G. C. A., Fontana, V., & Pirmohamed, M. (2023) · Frontiers in Microbiomes · doi:10.3389/frmbi.2023.1061193 · Cited by 6
“antecedent autoantibodies or greater complement-mediated inflammation (Callahan et al., 2011; Iwama et al., 2014; Harbour et al., 2015; Caturegli et al., 2016; Johnson et al., 2016; Byrne and Fisher, 2017; Osorio et al., 2017; Postow et al., 2018).”
Haas, M., Lein, A., Fuereder, T., Schnoell, J., Brkic, F. F., Campion, N. J., Liu, D. T., Kadletz‐Wanke, L., Heiduschka, G., & Jank, B. J. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110799 · Cited by 5
Itonaga, T., Saito, K., Ikeda, N., & Mikami, R. (2020) · Acta Radiologica · doi:10.1177/0284185120916197 · Cited by 5
“Another retrospective study demonstrated that OS was longer in NSCLC patients with thyroid dysfunction, who were treated with pembrolizumab (9).”
BackgroundThyroid Dysfunction from Treatments for Solid Organ Cancers
Kotwal, A., & McLeod, D. S. A. (2022) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2021.12.006 · Cited by 5
Endocrine dysfunctions during treatment of immune-checkpoint inhibitors
Inaba, H., Ariyasu, H., Okuhira, H., Yamamoto, Y., Akamatsu, H., Katsuda, M., Jinnin, M., Hara, I., & Akamizu, T. (2020) · Trends in Immunotherapy · doi:10.24294/ti.v4.i1.606 · Cited by 5
One-size-fits-all dosing in oncology wastes money, innovation and lives
Norris, D. C. (2017) · Drug Discovery Today · doi:10.1016/j.drudis.2017.11.008 · Cited by 5
“…unthink-ingly into oncology practice , where one-size-fits-all dosing remains pervasive despite the steady accumulation of evidence dating back two decades [2] demonstrating that hematologic and other toxicities augur better outcomes from chemotherapy—and now from targeted therapies [3] as well.”
Thyroid dysfunction as a predictor of PD- 1/PD-L1 inhibitor efficacy in advanced lung cancer
Wang, Y., Ma, X., Ma, J., Li, J., Lin, Z., Gao, W., Gong, P., & Dai, P. (2025) · BMC Cancer · doi:10.1186/s12885-025-14097-w · Cited by 4
“Secondly, autoimmunity mediated by thyroid autoantibodies is also involved [23], but the mechanism of its occurrence is not exactly the same as that of autoimmune thyroiditis [24].”
Immune checkpoint inhibitors associated thyroiditis: mechanisms and clinical outcomes
Hammerstad, S. S., Lee, H. J., Tomer, Y., & Stefan–Lifshitz, M. (2025) · Journal of Endocrinological Investigation · doi:10.1007/s40618-025-02608-2 · Cited by 4
“Furthermore, preexisting thyroid autoimmunity appears to increase the risk of thyroid irAEs in patients treated with ICIs [25 , 42 , 68 ], suggesting shared immunological pathways between ICI-thyroiditis and AITD.”
Lung Toxicity from Immune Checkpoint Inhibitors: A Diagnostic Approach
Casal, A., Leiro‐Fernández, V., Villar-Aguilar, L., Casal-Guisande, M., Mosteiro, M., Botana‐Rial, M., Represas‐Represas, C., Torres‐Durán, M., & Fernández‐Villar, A. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14176133 · Cited by 4
“Retrospective studies indicate higher rates of cancer control in patients who experienced immune-related adverse effects [47].”
Fritzsch, A., Leucht, K., Röber, N., Conrad, K., Rothe, R., Wehner, R., Schumacher, U., Esteban, E., Barthélémy, P., Schmidinger, M., et al. (2025) · ESMO Open · doi:10.1016/j.esmoop.2025.105575 · Cited by 4
“21,22 23-27 Similarly, patients who developed diabetes on ICI treatment displayed antibodies reactive against islet cell antigen and glutamic acid decarboxylase-65.”
Abdallah, I. B., Guiu, S., Quantin, X., Jacot, W., & Viel, P. W. D. (2026) · Cancers · doi:10.3390/cancers18030358 · Cited by 4
“…mechanisms for the CMV–colitis association in this setting are the following [23]: pure CMV colitis in immunosuppressed patients due to chemotherapy and/or corticosteroids [24]; CMV reactivation triggered by immune-mediated colitis [25]; or mixed immune-mediated colitis with CMV superinfection.”
Mouri, A., Imai, H., Endo, S., Nakagawa, J., Tsukamoto, K., Kurata, Y., Yamaguchi, O., Masaki, K., Hashimoto, K., Shiono, A., et al. (2025) · Cancer Medicine · doi:10.1002/cam4.70741 · Cited by 4
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“However, in contrast to previous findings, we did not observe a significant asso - ciation between the presence of pre-existing antithyroid antibodies [14 – 16] or baseline TSH levels [17 – 20] and the occurrence of ICI-induced thyroid dysfunction.”
Chen, D., Saltos, A. N., Rose, T. A., Thompson, Z., Thapa, R., Chiappori, A., & Gray, J. E. (2023) · Cancers · doi:10.3390/cancers15092521 · Cited by 4
“The application has shown early AE associated with clinical outcomes [4,8,10,12–14,33,34], such as early irAE (2–6 weeks since initial treatment) in predicting responses to nivolumab in patients with NSCLC [14] and early AE (42 days after commencement of treatment) associated with improved survival in breast cancer pa…”
BackgroundInfluentialImmune-related thyroid dysfunction in patients with non-small cell lung cancer
Cai, C., Zhou, S., Qu, J., & Zhou, J. (2024) · Journal of Thoracic Disease · doi:10.21037/jtd-23-1092 · Cited by 4
“A prospective study conducted by Osorio et al. , of irTDs in patients with NSCLC receiving pembrolizumab showed an association between ATAs at baseline and irTDs (16).”
BackgroundMethodLu, D., Yao, J., Yuan, G., Gao, Y., Zhang, J., & Guo, X. (2024) · Endocrine · doi:10.1007/s12020-024-03949-3 · Cited by 4
“It was postulated in an observational study and a prospective study that the overall survival was prolonged when patients developed ICI-induced thyroid diseases after immunotherapy [27, 28].”
Immune Checkpoints and Their Inhibition in T-Cell Lymphomas
Seňavová, J., Rajmonová, A., Heřman, V., Jura, F., Velasova, A., Hamová, I., Tkachenko, A. S., Kupcová, K., & Havránek, O. (2024) · Folia Biologica · doi:10.14712/fb2024070030123 · Cited by 4
Organ-Specific Immune-Related Adverse Events for PD-1 Antibodies in Lung Cancer Treatment
Zheng, X., & Wei, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.628243 · Cited by 4
Endocrine adverse effects of immune checkpoint inhibitors
Walters, A. G. B., & Braatvedt, G. D. (2021) · Internal Medicine Journal · doi:10.1111/imj.14992 · Cited by 4
Thyroid disorders associated with immune control point inhibitors
Fidilio, E., Navarro-González, E., Romero-Lluch, A. R., Iglesias, P., Gómez, J. J. D., Apiñániz, E. A., Mazo, E. S., & Zafón, C. (2021) · Endocrinología Diabetes y Nutrición (English ed ) · doi:10.1016/j.endien.2021.10.004 · Cited by 4
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Endocrine immune-related adverse events: a double-edged sword?
Rengarajan, M., & Gainor, J. F. (2021) · Translational Lung Cancer Research · doi:10.21037/tlcr-2020-16 · Cited by 3
“After correcting for differences in the frequency of use across ICI agents, endocrine IRAEs were most likely to develop in patients on combination ipilimumab/nivolumab (64%), with lower rates observed among patients receiving PD-1 (16%) or PD-L1 (20%) inhibitor monotherapy, consistent with observations from earlier st…”
BackgroundResultInfluentialCosting ‘the’ MTDPreprint
Norris, D. C. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/150821 · Cited by 4
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“[29 ,31] However, toxicities such as pneumonitis [32,33], cytopenia [34], encephalitis, hepatitis, myocarditis [35], and severe irAEs occurring in older patients [12] are associated with worse survival.”
Pollack, R. M., Stokar, J., Lishinsky-Fischer, N., Gurt, I., Kaisar-Iluz, N., Shaul, M. E., Fridlender, Z. G., & Dresner–Pollak, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310526 · Cited by 3
Pellitero, A. M., García, M. Z., Ruiz, M. G., Arbonés-Mainar, J. M., del Prado, R. L., & Isla, D. (2024) · World Journal of Oncology · doi:10.14740/wjon1790 · Cited by 3
“Some of the most frequent irAEs, specifically of pembroli-zumab, are thyroid disorders, as demonstrated by Sugano et al in their study, which correlated with increased PFS [24, 25].”
BackgroundT3 and T4 autoantibodies: emerging biomarkers for evaluating thyroid disorders
Liu, J., Mao, C., Mao, X., Wang, X., Zheng, T., Dong, L., & Mao, Y. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1537222 · Cited by 3
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“33 – 35 However, a recent publication by Goodman et al . highlights the importance of steroid timing, particularly shortly after ICI initiation, as it impairs lymphocyte counts and is associated with poor ICI responses over the duration of steroid use.”
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“In addition, relatively small studies found that patients who developed skin disorders (24, 26–29), thyroiditis (25, 27, 30–32), and endocrine disorders (24) had a better prognosis, whereas those who developed pneumonitis (27, 33, 34) requiring cessation or interruption of ICI treatment and changes…”
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Metadata
- Authors
- Osorio, J. C., Ni, A., Chaft, J. E., Pollina, R., Kasler, M. K., Stephens, D., Rodriguez, C., Cambridge, L., Rizvi, H., Wolchok, J. D., Merghoub, T., Rudin, C. M., Fish, S., & Hellmann, M. D.
- Affiliations
- Weill Cornell Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Hellmann, M.D.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 28
- Issue
- 3
- Pages
- 583-589
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC5834017
- OpenAlex
- W2561156916
- Cited by
- 659
- References
- 26
- Citations by year
- 2026: 23 · 2025: 50 · 2024: 70 · 2023: 75 · 2022: 102 · 2021: 95 · 2020: 98 · 2019: 77 · 2018: 51 · 2017: 17
- FWCI
- 26.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P30 CA008748)
- Fiona and Stanley Druckenmiller Center for Lung Cancer Research
- KEYNOTE-001 (NCT01295827)
- Merck Sharp & Dohme, a subsidiary of Merck
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Clinical Neurology › Autoimmune Neurological Disorders and Treatments
- Keywords
- immune-related adverse events, anti-thyroid antibodies, pembrolizumab, anti-PD-1 therapy, non-small cell lung cancer, hypothyroidism, hyperthyroidism, humoral immunity, immune checkpoint inhibitors, progression-free survival, overall survival
- MeSH terms
- Adolescent, Adult, Aged, Antibodies, Monoclonal, Carcinoma, Non-Small-Cell Lung, Female, Humans, Hyperthyroidism, Male, Middle Aged, Neoplasm Staging, T-Lymphocytes, Thyroid Gland, Disease-Free Survival, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized, Drug-Related Side Effects and Adverse Reactions
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