LSD1 Inhibition Induces MHC-I and Dendritic Cell Activation to Promote Antitumor Immunity in Head and Neck Squamous Cell Carcinoma

Abstract Poor infiltration of CD8+ T cells and dysregulation of MHC class I (MHC-I) confer resistance to anticancer immunotherapies. Inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been shown to increase CD8+ T-cell infiltration in head and neck squamous cell carcinoma (HNSCC). In this study, we aimed to elucidate the mechanisms of LSD1 inhibition in antitumor immunity in HNSCC to aid in the development of effective therapeutic strategies. LSD1 inhibition in syngeneic and chronic tobacco carcinogen–induced HNSCC mouse models increased the recruitment of activated dendritic cells (DC), as well as CD4+ and CD8+ T cells, and the expression of IFNγ in CD8+ T cells, CXCL9 in DCs, and CXCR3 in CD4+ T cells. Humanized HNSCC mice and patient data validated the inverse correlation of KDM1A with DC markers, CD8+ T cells, and their activating chemokines. Kdm1a knockout in mouse HNSCC and LSD1 inhibitor treatment of human HNSCC cells cocultured with human peripheral blood mononuclear cells resulted in MHC-I upregulation in cancer cells. LSD1 inhibition promoted CD8+ T-cell activation via a DC-dependent mechanism and induced efficient antigen presentation in CD8+ T cells. Finally, LSD1 inhibition increased H3K4me2 at the promoters of DC-related markers (BATF3 and CXCL9), T-cell markers (CXCR3), and MHC-I (HLA-A). Overall, LSD1 inhibition in tumor cells upregulates MHC-I expression and stimulates CXCL9 secretion by DCs to enhance antigen presentation and promote CD8+ T-cell activation via the CXCL9–CXCR3 signaling axis, resulting in increased IFNγ production. This may have implications for treating poorly immunogenic and immunotherapy-resistant cancers. Significance: LSD1 inhibition enhances antigen presentation and reprograms the tumor microenvironment by inducing infiltration of T cells and dendritic cells, activating antitumor immunity and providing an epigenetic therapy for head and neck cancer.