LSD1 orchestrates retinoid-immune crosstalk to balance homeostasis and cancer

Summary: Abstract Body: Precise regulation of retinoic acid metabolism is critical for tissue homeostasis, yet the context-dependent mechanisms by which this occurs remain incompletely understood. Here, we show that histone lysine-specific demethylase 1 (LSD1, also known as KDM1A) is a previously unappreciated epigenetic brake on retinoid responses in skin. We find that epidermal Lsd1 is essential for embryonic skin development and survival, while deletion in adult epidermis is tolerated, provoking retinoid signaling activation and immune cell infiltration. At the chromatin regulatory level, we show that Lsd1 directly binds to retinoid metabolism and immune chemokine loci in keratinocytes and correspondingly, Lsd1 loss increases H3K4me2 at these same loci. We then leverage single cell resolution spatial profiling and time-course studies to demonstrate that Lsd1 loss leads to early activation of retinoid signaling in certain keratinocyte subsets followed by migration of dendritic cells (DCs) to recruit CD4+ T cells to the skin. Strikingly, topical catalytic Lsd1 inhibition (Lsd1i) recapitulates this phenotype, and we observe that retinoic acid receptor antagonism prevents Lsd1i effects. Finally, we reveal that topical Lsd1i restricts skin tumor growth in two independent cancer models and is associated with enhanced keratinocyte-DC signaling markers. Overall, our data open therapeutic avenues for leveraging this crosstalk observed upon Lsd1i in keratinocyte cancers, the most common of all malignancies. Nina Kuprasertkul^{1, 2}, Brian Capell^{1, 2} 1. Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. 2. Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. Cell Communication Networks and Stromal Biology