Abstract
SummaryCytotoxic T lymphocyte-associated antigen-4 (CTLA-4), the first immune checkpoint to be targeted clinically, has provided an effective treatment option for various malignancies. However, the clinical advantages associated with CTLA-4 inhibitors can be offset by the potentially severe immune-related adverse events (IRAEs), including autoimmune thyroid dysfunction. To investigate the candidate genes and signaling pathways involving in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy, integrated differentially expressed genes (DEGs) were extracted from the intersection of genes from Gene Expression Omnibus (GEO) datasets and text mining. The functional enrichment was performed by gene ontology (GO) annotation and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Protein-protein interaction (PPI) network, module enrichment, and hub gene identification were constructed and visualized by the online Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. A total of 22 and 17 integrated human DEGs in hypothyroidism and hyperthyroidism group related to anti-CTLA-4 therapy were identified, respectively. Functional enrichment analysis revealed 24 GO terms and 1 KEGG pathways in the hypothyroid group and 21 GO terms and 2 KEGG pathways in the hyperthyroid group. After PPI network construction, the top five hub genes associated with hypothyroidism were extracted, including ALB, MAPK1, SPP1, PPARG, and MIF, whereas those associated with hyperthyroidism were ALB, FCGR2B, CD44, LCN2, and CD74. The identification of the candidate key genes and enriched signaling pathways provides potential biomarkers for autoimmune thyroid dysfunction related to anti-CTLA-4 therapy and might contribute to the future diagnosis and management of IRAEs for cancer patients.
Highlights
Immune checkpoint blockade represents one of the most promising anti-tumor immunotherapeutic strategies
475 differentially expressed genes (DEGs) between hyperthyroid samples and normal controls were defined from the Database for Annotation Visualization and Integrated Discovery (DAVID) was utilized to perform gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis based on the integrated DEGs achieved above
In the results of GO analysis, 10 biological process (BP) terms, 10 cell component (CC) terms, and 4 molecular function (MF) terms were identified in the integrated DEGs of hypothyroidism with a P value < 0.05 as the significant threshold. 5 genes were mainly enriched in the BP term “negative regulation of apoptotic process”, 12 genes fell into in the CC term “extracellular exosome” and 7 genes were involved in the MF term “identical protein binding” (Fig. 4 and S.Table 3a)
Summary
Immune checkpoint blockade represents one of the most promising anti-tumor immunotherapeutic strategies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), as a key negative regulator of T cell responses, is the first immune checkpoint to be clinically targeted in oncology [1]. CTLA-4 is a type 1 transmembrane glycoprotein of the immunoglobin superfamily and shares 31% amino acid identity with CD28 [2]. It inhibits T cell activity by competing with CD28 for B7 engagement and delivering an inhibitory signal directly from its cytoplasmic tail [3]. Anti-CTLA-4 antibodies, such as ipilimumab and tremelimumab, can exert their antitumor effects via activating CD8 + effector T cells and modulating the function of CD4 + T cells [1]. Ipilimumab alone, or in combination with nivolumab has Invest New Drugs (2020) 38:1717–1729 shown overall survival benefits in patients suffering from metastatic melanoma, metastatic renal cell carcinoma, and other malignancies [4, 5]
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