Checkpoint Blockade-Induced Dermatitis and Colitis Are Dominated by Tissue-Resident Memory T Cells and Th1/Tc1...

Area of Science:

• Immunology
• Oncology
• Dermatology

Background:

• Immune checkpoint blockade (ICB) offers therapeutic success in various cancers.
• Immune-related adverse events (irAEs) are common, potentially severe side effects of ICB.
• Understanding irAE immunologic mechanisms is crucial for developing novel therapeutic targets.

Purpose of the Study:

• To investigate the immunologic mechanisms underlying irAE dermatitis.
• To compare the immune cell profiles of irAE dermatitis with psoriasis and colitis.

Main Methods:

• Multiparameter immunofluorescence (IF) for cell identification.
• Spatial transcriptomics to analyze gene expression in specific tissue regions.
• RNA in situ hybridization (RISH) to confirm gene and protein expression.

Main Results:

• Cutaneous irAEs showed preferential expansion of CD4+ and CD8+ tissue-resident memory T (TRM) cells.
• Spatial transcriptomics revealed a Th1-associated gene expression profile in irAEs, distinct from the Th17 profile in psoriasis.
• IFNγ, CXCL9, CXCL10, and TNFα were expressed in irAE dermatitis, with IFNγ localized to TRM cells.
• A Th1-skewed phenotype was also observed in irAE colitis.

Conclusions:

• Immune-related adverse events are characterized by Th1-skewed inflammation driven by tissue-resident memory T cells.
• These findings highlight potential therapeutic targets for managing irAEs.
• The study provides insights into the distinct immunologic pathways of irAEs compared to other inflammatory conditions.