Immunosensitivity mediated by downregulated AKT1-SKP2 induces anti-PD-1-associated thyroid immune injury

• Published in: International immunopharmacology 2023-08, Vol.121, p.110452-110452, Article 110452
• Main Authors: Wu, Yanmeizhi, Li, Jingjing, Yang, Xu, Hou, Boyu, Qiao, Hong
• Format: Article
• Language: English
• Subjects: AKT1; Anti-PD-1; CD8+T cells; PD-L1; SKP2; Thyroid irAE
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.110452

•Anti-PD-1-associated thyroid immune damage is associated with women, IgG4 subtypes of drugs, the baseline and changes in thyroid function, antibodies, and hormone sensitivity.•Head and neck cancers have the highest risk of thyroid irAE, which may be associated with squamous carcinoma.•Those with abundant peripheral blood lymphocytes before treatment are susceptible to irAE hypothyroidism; those with significant lymphocytosis before and after treatment are susceptible to irAE hyperthyroidism and thyroiditis.•Anti-PD-1 increases the immunosensitivity of thyroid cells by downregulating AKT1-SKP2 and inducing thyroid irAE. Immune checkpoint inhibitors evoke the immune system, which may cause immune-related adverse effects. The predictors and mechanisms of anti-PD-1-associated thyroid immune injury remain unclear. A retrospective analysis is conducted on 518 patients treated with anti PD-1/PD-L1. Firstly, the differences between anti PD-1 and anti PD-L1 are compared on the risk of thyroid immune injury. Then, the predictors of the risk and thyroid function for anti PD-1 related thyroid immune injury are analyzed. Furthermore, the in vitro mechanism of normal thyroid cells (NTHY) is studied. First, the effect of anti PD-1 on the cell viability and immune sensitivity of thyroid cells is observed. Cell viability includes cell proliferation, apoptosis, cell cycle, T4 secretion, while immune sensitivity includes molecular expression and CD8 + T cell aggregation and killing towards NTHY. Then the differentially expressed proteins (DEPs) are screened by protein mass spectrometry. Enrichment of KEGG pathway and annotation of GO function on DEPs are conducted. Human protein–protein interactions are obtained from STRING database. The network is constructed and analyzed using Cytoscape software. In vitro, key proteins and their pathways are validated through overexpression plasmids or inhibitors. The recovery experiment and the immuno-coprecipitation experiment are designed to support the results. In vivo, the key proteins are detected in the thyroid tissue of mice fed with anti PD-1, as well as in the thyroid tissue of patients with Hashimoto's thyroiditis. Thyroid irAE is associated with female, IgG, FT4, TPOAb, TGAb, TSHI, TFQI, and TSH. Peripheral lymphocytes are associated with thyroid function. In vitro, the NIVO group shows prologed G1 phase, decreased FT4, downregulated PD-L1, upregulated IFN-γ, and more CD8 + T cell infiltration and cytotoxicity. AKT1-SKP2 is ch