LSD1 inhibition promotes CD8+ T cells mediated anti-tumor immunity by MHC-I upregulation and enhanced infiltration of dendritic cells through IFNγ-CXCL9-CXCR3 axis

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.