Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

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 (irAEs) 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 break-down of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Tregs) 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+CD25+CD127– 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 propose an inflammatory Treg reprogramming as a feature of immunotherapy-induced irAEs, that may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001005446	Tregs were sorted as CD4+CD25+CD127- cells from peripheral blood of 14 healthy individuals, 8 patients with mild/severe rheumatoid arthritis, 1 patient with systemic lupus erythematosus/rheumatoid arthritis, 2 patients with ulcerative colitis and 2 patients with Chrohn's disease. RNA was extracted and polyA libraries were prepared using the Illumina Truseq sample preparation kit v.2. Single-end 75bp sequencing was performed on NextSeq500.	NextSeq 500	27
EGAD00001006415	Tregs were sorted as CD4+CD25+CD127- cells from peripheral blood of patients with advanced metastatic melanoma, stage III(B-D)-IV, who were receiving treatment with anti-PD1 (n =26); and patients with kidney, non-small cell lung, liver and bladder cancer who were receiving treatment with anti-PD1. RNA was extracted and polyA libraries were prepared using the Illumina Truseq sample preparation kit v.2. Single-end sequencing was performed on NextSeq500.	NextSeq 500	49

Publications	Citations
Regulatory T-cell Transcriptomic Reprogramming Characterizes Adverse Events by Checkpoint Inhibitors in Solid Tumors. Grigoriou M, Banos A, Hatzioannou A, Kloetgen A, Kouzis P, Aggouraki D, Zakopoulou R, Bamias G, Kassi E, Mavroudis D, Bamias A, Boumpas DT, Tsirigos A, Gogas H, Alissafi T, Verginis P. Cancer Immunol Res 9: 2021 726-734	21