Abstract
Poor infiltration of CD8+ T cells and dysregulation of major histocompatibility complex 1 (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 recruitment of activated dendritic cells (DCs), as well as CD4+ and CD8+ T cells, and expression of interferon-gamma (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 co-cultured 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. 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.