Regulatory T-cell Transcriptomic Reprogramming Characterizes Adverse Events by Checkpoint Inhibitors in Solid Tumors

Area of Science:

• Immunology
• Oncology
• Autoimmunity

Background:

• Immune checkpoint inhibitors (ICI) have transformed cancer treatment by enhancing antitumor responses.
• However, a significant number of patients develop immune-related adverse events (irAEs) that mimic autoimmune diseases, complicating treatment.
• The underlying mechanisms causing irAEs and the breakdown of self-tolerance remain largely unknown.

Purpose of the Study:

• To investigate the role of regulatory T cells (Tregs) in the development of irAEs following ICI therapy.
• To identify molecular signatures of Tregs in patients experiencing irAEs.

Main Methods:

• Transcriptomic analysis of CD4+CD25+CD127- Tregs from patients with advanced metastatic melanoma who developed irAEs after ICI immunotherapy.
• Comparison of Treg signatures across different cancer types with irAEs and in patients with autoimmune diseases.

Main Results:

• Tregs from patients with irAEs exhibit significant transcriptomic reprogramming.
• A distinct inflammatory, apoptotic, and metabolic signature was identified in these Tregs.
• This inflammatory Treg signature is conserved across different cancers and in patients with autoimmune diseases.

Conclusions:

• Inflammatory reprogramming of Tregs is a key feature of immunotherapy-induced irAEs.
• Understanding these Treg alterations may lead to strategies for maintaining peripheral tolerance during cancer immunotherapy.
• This research could pave the way for developing more effective cancer immunotherapies with reduced autoimmune side effects.