LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade

Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy. [Display omitted] •ERV induction and RISC reduction activate dsRNA-IFN pathway upon LSD1 inhibition•LSD1 loss in tumor cells stimulates anti-tumor T cell immunity•LSD1 ablation enhances tumor immunogenicity and T cell infiltration•LSD1 inhibition overcomes resistance to anti-PD-1 therapy in a mouse melanoma model Ablating the histone demethylase LSD1 genetically or pharmacologically enhances tumor immunogenicity by stimulating endogenous retrovirus expression and downregulating RNA-induced silencing complex, supporting the promise of LSD1 inhibition in overcoming resistance to checkpoint blockade in cancer treatment.