Retrospective Study Of Thyroid Dysfunction Associated With Immune Checkpoint Inhibitor Therapy And Preliminary Discussion Of Related Mechanism

Part Ⅰ:Thyroid dysfunction after immune checkpoint inhibitor treatment in a single-center Chinese cohort:a retrospective studyBackground:Thyroid dysfunction is a common adverse event after immune checkpoint inhibitor(ICI)therapy.The clinical manifestations of thyroid immune-related adverse event(irAE)are variable and the relevant data is still blank in China.Our study aimed to identify the clinical and biochemical characteristics of Chinese patients with ICI-related thyroid dysfunction.Methods:We retrospectively reviewed patients with carcinoma who received ICI therapy and underwent evaluation of thyroid function during hospitalization at Peking Union Medical College Hospital between January 1,2017 and December 31,2020.Clinical and biochemical features were analyzed in patients who developed ICI-related thyroid dysfunction.Survival analyses were performed to determine the effect of thyroid autoantibodies on thyroid abnormalities and the impact of thyroid irAE on clinical outcomes.Results:The cohort included 270 patients with a median follow-up of 17.7 months;120(44%)of these patients developed thyroid dysfunction on immunotherapy.The most common thyroid irAE was overt hypothyroidism(with/without transient thyrotoxicosis),which occurred in 38%of patients with thyroid irAE(n=45),followed by subclinical thyrotoxicosis(n=42),subclinical hypothyroidism(n=27),and isolated overt thyrotoxicosis(n=6).The median time to first clinical presentation was 49 days(interquartile range 23,93)for thyrotoxicosis and 98 days(interquartile range 51,172)for hypothyroidism.In patients treated with PD-1 inhibitors,hypothyroidism was strongly associated with younger age(odds ratio[OR]0.44,95%confidence interval[CI]0.29-0.67;P<0.001),previous thyroid disease(OR 4.30,95%CI 1.54-11.99;P=0.005),and a higher baseline thyroid-stimulating hormone level(OR 2.76,95%CI 1.80-4.23;P<0.001).Thyrotoxicosis was only associated with the baseline thyroid-stimulating hormone(TSH)level(OR 0.59,95%CI 0.37-0.94;P=0.025).Thyroid dysfunction after initiation of ICI therapy was associated with better progression free survival(hazard ratio[HR]0.61,95%CI 0.44-0.86;P=0.005)and overall survival(hazard ratio 0.67,95%CI 0.45-0.99;P=0.046).Anti-thyroglobulin antibody positivity increased the risk of thyroid irAE.Conclusions:The occurrence of thyroid irAEs with diverse phenotypes is common.The clinical characteristics of ICI-related thyroid dysfunction among the Chinese population in this study were basically similar to those observed in other regions.Distinct clinical and biochemical characteristics suggest heterogeneity among different subgroups of thyroid dysfunction,which requires further research to explore the under mechanism.Part Ⅱ:Exploring the Mechanisms of Immune Checkpoint InhibitorRelated Thyroid Dysfunction through Single-Cell Sequencing Analysis Background:Immune-related thyroid dysfunction is a common adverse event associated with the use of immune checkpoint inhibitors,particularly PD-1 and PD-L1 inhibitors.However,the underlying mechanisms of its occurrence are not fully understood,and it may differ from the pathogenesis of chronic lymphocytic thyroiditis as previous clinical studies.Traditional techniques such as flow cytometry can only provide information on the quantity and proportion of different immune cell subsets,but cannot capture changes in immune cell transcriptomes.Single-cell sequencing allows for investigation of immune cell characteristics in thyroid tissue related to immune-related adverse events(irAEs)at the level of individual cells,providing reliable information for potential mechanisms of irAEs.In this study,we used single-cell sequencing technology to obtain transcriptomic changes in immune cells in thyroid tissue which irAE occurs,aiming to explore the underlying mechanisms of thyroid irAEs.Methods:Transcriptomic information from thyroid tissue samples with irAEs was obtained,and gene expression characteristics and pathway enrichment analysis were performed to identify immune cell subset characteristics in thyroid tissue.Based on the single-cell transcriptomic data,the activation status of the JAK-STAT pathway in thyroid irAE tissue was further investigated.Results:CD4+T cells,NK cells,macrophages,and neutrophils were significantly increased in thyroid tissue with irAEs,and CD8+T cell exhaustion was not observed.Chemokines CCL4 and CCL5 were significantly downregulated,while TNFSF8,TNFSF9,TGFB1,CXCL8,CXCL13,and CXCL16 were significantly upregulated in thyroid irAE tissue.Expression levels of JAK-STAT pathway-related genes were significantly increased.Conclusion:Immune cells in thyroid irAE tissue exhibit increased toxicity and proinflammatory function,and the JAK-STAT pathway was activated.Part Ⅲ:A real-world study of thyroid dysfunction associated with ICI combined with VEGFR-TKI therapy based on the FAERS databaseBackground:Due to limited clinical benefits of immune checkpoint inhibitor(ICI)in some types of tumors,combination therapy of ICI with vascular endothelial growth factor receptor tyrosine kinase inhibitor(VEGFR-TKI)has been approved as a first-line treatment for certain malignancies.However,both drugs share overlapping adverse event effects,including thyroid dysfunction,as confirmed by real-world studies.The aim of this study was to investigate the relationship between thyroid dysfunction and the combined treatment of ICI and VEGFRTKI by data mining algorithms,and compare it with ICI monotherapy.Methods:Four data mining algorithms were employed to detect signals of thyroid dysfunction associated with ICI monotherapy and ICI combined with VEGFR-TKI therapy.The data from 72 quarters in the Food and Drug Administration Adverse Event Reporting System(FAERS)database.Statistical analysis was performed using MySQL Workbench and SPSS 25.0 version.Four data mining algorithms were used to detect signals of thyroid dysfunction associated with ICI therapy alone versus ICI combined with VEGFR-TKI treatment,and logestic regression was used to analyze risk factors for the occurrence of reported deaths.Results:A total of 43,284 reports of thyroid dysfunction adverse events were retrieved,of which 3,747 reports listed ICI as the primary suspect drug,and 285 reports listed ICI or VEGFR-TKI as the primary suspect drug in combination therapy with the other drug.All four algorithms indicated strong signals of thyroid dysfunction associated with combination of ICI and VEGFR-TKI therapy.Elder patients(odds ratio[OR]1.50,95%confidence interval[CI]1.21-1.85,P<0.001)and the occurrence of treatment-related hypothyroidism(OR 3.57,95%CI 2.58-4.93,P<0.001)were risk factors for death reports,but combination therapy did not increase the risk of death events compared to ICI monotherapy(OR 0.68,95%CI 0.431.07,P=0.096).Conclusion:This study identified drug safety signals of thyroid dysfunction associated with the treatment of ICI combined with VEGFR-TKI by FAERS database.Early identification and management of thyroid dysfunction among patients with combination treatment of ICI and VEGFR-TKI.It was observed that combination therapy did not increase the risk of mortality compared to monotherapy with ICI.