Inhibiting LSD1 unlocks retinoid AP-1 programming to activate epithelial immunity and skin tumor suppression

Area of Science:

• Immunology
• Dermatology
• Epigenetics

Background:

• Lysine-specific demethylase 1 (LSD1; KDM1A) regulates gene expression through chromatin modification.
• Its role in epithelial immunity, particularly in the skin, is not well understood.

Purpose of the Study:

• To investigate LSD1's function in epidermal immunity and its potential as a therapeutic target for skin cancer.
• To determine if LSD1 inhibition can enhance anti-tumor immune responses in the skin.

Main Methods:

• CUT&RUN profiling to map LSD1 binding sites and histone modifications.
• Single-cell spatial analyses to study cellular interactions and signaling pathways.
• In vivo studies using mouse models of cutaneous squamous cell carcinoma.

Main Results:

• LSD1 acts as a brake on retinoid and AP-1-driven enhancer activity in the epidermis.
• Topical LSD1 inhibition in adult skin is tolerated and activates immune signaling pathways.
• LSD1 inhibition suppresses skin tumors by enhancing keratinocyte-immune crosstalk, particularly CD4+ T cell responses.

Conclusions:

• LSD1 is a key repressor of epithelial immune competence in the skin.
• LSD1 inhibition represents a promising therapeutic strategy for skin cancer by activating anti-tumor immunity.