Immune-Related Cutaneous Adverse Events Display Distinct Clinical and Molecular Characteristics, Depending on Immune...

Area of Science:

• Oncology
• Immunology
• Dermatology
• Pharmacology

Background:

• Immune-related cutaneous adverse events (ircAEs) are frequent complications of cancer immunotherapy, offering insights into broader immune-related adverse events (irAEs).
• Understanding the molecular basis of 7ircAEs is crucial for managing immunotherapy side effects and maintaining treatment efficacy.
• Maculopapular rash (MPR) and toxic epidermal necrolysis (TEN) serve as clinical models for investigating ircAEs due to their similar presentation.

Purpose of the Study:

• To characterize the distinct molecular and cellular signatures of ircAEs arising from single-agent PD1 and combined PD1+CTLA4 (P+C) immunotherapy regimens.
• To compare the transcriptomic and immune infiltrates of ircAEs with those of MPR and TEN.
• To elucidate how different immunotherapy strategies influence the development of cutaneous adverse events.

Main Methods:

• Transcriptomic analysis of skin biopsies from patients experiencing ircAEs, MPR, TEN, and healthy controls.
• Multiplexed immunohistochemistry to assess immune cell infiltrates in the skin.
• Principal component analysis (PCA) for transcriptomic data comparison and PERMANOVA for immune infiltrate analysis.

Main Results:

• Distinct transcriptomic profiles were observed: PD1-associated ircAEs clustered with TEN, showing upregulation of Type-I-response genes (e.g., CXCL9, CXCL10).
• P+C immunotherapy-associated ircAEs exhibited a gene expression profile more similar to MPR.
• Significant differences in immune infiltrates were found across all groups, with abundant CD4 T-cells in ircAE dermis; PD1 expression was notably higher on CD4 cells in PD1 monotherapy compared to other groups.

Conclusions:

• PD1 monotherapy-induced ircAEs share molecular similarities with the cytotoxic profile of TEN.
• Combined P+C immunotherapy-associated ircAEs more closely mirror the characteristics of MPR.
• These findings highlight the need for tailored management strategies for ircAEs, promoting personalized approaches to optimize cancer immunotherapy while minimizing treatment interruptions.