T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Severe immune-related adverse events (irAEs) affect up to 60% of melanoma patients treated with immune checkpoint inhibitors (ICIs).
• The underlying immunological predictors of irAE development remain largely unknown.
• Understanding these predictors is crucial for managing ICI-induced toxicity.

Purpose of the Study:

• To identify baseline immunological factors in peripheral blood associated with severe irAE development in melanoma patients undergoing ICI therapy.
• To explore the relationship between T cell receptor (TCR) clonality and irAEs during combination ICI treatment.

Main Methods:

• Mass cytometry by time of flight, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing, and bulk TCR sequencing were employed.
• Analysis of 93 pre- and early on-ICI peripheral blood samples from three patient cohorts (n=27, 26, 18).
• Investigated circulating T cell characteristics and TCR diversity.

Main Results:

• Two pretreatment factors—activated CD4 memory T cell abundance and TCR diversity—were significantly associated with severe irAE development.
• These associations were independent of the specific organ system affected by irAEs.
• On-treatment TCR clonality changes were explored in relation to irAE severity and timing.

Conclusions:

• Circulating T cell characteristics at baseline can predict the development of severe irAEs in patients treated with ICIs.
• These findings have implications for improved diagnostics and clinical management of ICI-induced toxicity.
• Further research can leverage these biomarkers for personalized treatment strategies.