LSD1 Inhibition eliminates HNSCC coordinated by activated Dendritic Cells, IFNg-CXCL9-CXCR3 and MHC-I

Poor infiltration of CD8+ cells and dysregulated MHC-I provide resistance to anti-cancer clinical therapies. This study aimed to uncover mechanisms of lysine-specific demethylase 1 (Kdm1a or LSD1) in antitumor immunity in Head and Neck Squamous cell carcinoma (HNSCC). LSD1 inhibition in syngeneic and chronic tobacco carcinogen-induced HNSCC mice recruited an activated dendritic cell (DCs), CD4+, and CD8+ T cells, enriched IFNγ in T cells, CXCL9 in DCs, and CXCR3 in T cells, evaluated by single cell RNA-seq analysis. Humanized HNSCC mice and TCGA data validate inverse correlation of Kdm1a with markers of DCs, CD8+ T cells, and their activating chemokines. LSD1 knockout or inhibitors in mouse HNSCC and co-culture showed MHC-I upregulation in tumors for efficient antigen presentation. Overall, LSD1 inhibition promoted DCs through IFNγ-CXCL9-CXCR3 axis and MHC-I upregulation in tumors to induce CD8+ T cell medicated antitumor immunity, which has implications for poorly immunogenic and immunotherapy-resistant cancers therapy. C57BL/6J mice were treated with 4-Nitroquinoline 1-oxide (4NQO) for 16 weeks, and at week 20, divided into three groups (n=6) and subjected to different treatments: group 1) vehicle; 2) 4NQO; 3) 4NQO+SP2509. At the time of sacrifice, tongue tumors were cut to prepare single-cell suspensions, followed by scRNA-seq analysis of 8000 cells/mouse (n=2/condition) using a 10X genomics kit according to the manufacturer's recommendations.