LSD1 ablation promotes mammary tumor metastasis by attenuating NK cell-mediated anti-tumor immunity

Epigenetic deregulation can alter the expression of cancer-related genes in tumor cells and may promote metastasis by influencing interactions between tumor cells and their immune microenvironment. However, the underlying immune mechanisms remain poorly understood. LSD1 (KDM1A) is a histone demethylase that has been proposed to function as a tumor and metastasis suppressor in breast cancer. Here, using the MMTV-PyMT breast cancer mouse model, we show that natural killer (NK) cells play a critical role in suppressing tumor cell metastasis to the lung, and that ablation of LSD1 leads to increased lung metastasis. This phenotype is accompanied by pronounced upregulation of immune-related genes, including major histocompatibility complex class I (MHC-I) genes, in tumor cells and by extensive remodeling of the tumor immune microenvironment, characterized by reduced abundance and maturation of NK cells. Consistent with these observations, NK cells exhibit reduced cytotoxicity toward Lsd1-null PyMT tumor cells. Notably, NK cell-mediated killing can be restored by disrupting expression of the non-classical MHC-I molecule Qa-1, a ligand for the inhibitory NK receptor CD94/NKG2A, in tumor cells. In transplantation experiments, Lsd1-null PyMT tumor cells formed significantly larger lung metastatic lesions than Lsd1-wildtype tumor cells in SCID mice, which possess functional NK cells, but not in NSG mice that lack NK cells. Collectively, these findings suggest that epigenetic deregulation in LSD1-deficient mammary tumor cells reprograms the tumor immune microenvironment, resulting in impaired NK cell-mediated tumor surveillance and enhanced metastatic progression.