@article{2999836,
    title = "Regulatory T-cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors",
    author = "Grigoriou, M. and Banos, A. and Hatzioannou, A. and Kloetgen, A. and Kouzis, P. and Aggouraki, D. and Zakopoulou, R. and Bamias, G. and Kassi, E. and Mavroudis, D. and Bamias, A. and Boumpas, D.T. and Tsirigos, A. and Gogas, H. and Alissafi, T. and Verginis, P.",
    journal = "Cancer Immunology Research",
    year = "2021",
    volume = "9",
    number = "7",
    pages = "726-734",
    publisher = "American Association for Cancer Research Inc.",
    issn = "2326-6066, 2326-6074",
    doi = "10.1158/2326-6066.CIR-20-0969",
    keywords = "cytokine;  nivolumab;  pembrolizumab;  thyroxine;  transcriptome, advanced cancer;  apoptosis;  Article;  bladder cancer;  cancer immunotherapy;  CD4+ CD25+ T lymphocyte;  clinical article;  controlled study;  Crohn disease;  data analysis software;  Hashimoto disease;  human;  human cell;  immunological tolerance;  immunopathology;  inflammation;  kidney cancer;  liver cancer;  metabolism;  metastatic melanoma;  multiple cycle treatment;  non small cell lung cancer;  regulatory T lymphocyte;  rheumatoid arthritis;  solid malignant neoplasm;  transcriptomics;  ulcerative colitis;  adult;  adverse drug reaction;  adverse event;  aged;  blood;  drug effect;  female;  genetics;  immunology;  immunophenotyping;  male;  melanoma;  middle aged;  pathology;  regulatory T lymphocyte;  skin tumor;  very elderly;  young adult, Adult;  Aged;  Aged, 80 and over;  Drug-Related Side Effects and Adverse Reactions;  Female;  Humans;  Immune Checkpoint Inhibitors;  Immune Checkpoint Proteins;  Immune Tolerance;  Immunophenotyping;  Male;  Melanoma;  Middle Aged;  RNA-Seq;  Skin Neoplasms;  T-Lymphocytes, Regulatory;  Transcriptome;  Young Adult",
    abstract = "Immune checkpoint inhibitors (ICI), which target immune regulatory pathways to unleash antitumor responses, have revolutionized cancer immunotherapy. Despite the remarkable success of ICI immunotherapy, a significant proportion of patients whose tumors respond to these treatments develop immune-related adverse events (irAE) resembling autoimmune diseases. Although the clinical spectrum of irAEs is well characterized, their successful management remains empiric. This is in part because the pathogenic mechanisms involved in the breakdown of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Treg) in individuals with irAEs because these cells are vital for maintenance of peripheral tolerance, appear expanded in the peripheral blood of individuals with cancer, and abundantly express checkpoint molecules, hence representing direct targets of ICI immunotherapy. Our data demonstrate an intense transcriptomic reprogramming of CD4+ Tregs in the blood of individuals with advanced metastatic melanoma who develop irAEs following ICI immunotherapy, with a characteristic inflammatory, apoptotic, and metabolic signature. This inflammatory signature was shared by Tregs from individuals with different types of cancer developing irAEs and individuals with autoimmune diseases. Our findings suggest that inflammatory Treg reprogramming is a feature of immunotherapy- induced irAEs, and this may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance. © 2021 American Association for Cancer Research."
}