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LSD1 ablation promotes mammary tumor metastasis by attenuating NK cell-mediated anti-tumor immunity
Dongxi Xiang1,2, Sen Han1,2, Aina He1,2,3
1Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Abstract:
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.
Insights
Epigenetic changes affecting LSD1 (KDM1A) in breast cancer cells impair natural killer (NK) cell surveillance, promoting lung metastasis. Restoring NK cell function by targeting Qa-1 can inhibit tumor spread.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Epigenetic deregulation influences cancer-related genes and the tumor immune microenvironment, potentially promoting metastasis.
- LSD1 (KDM1A), a histone demethylase, is implicated as a tumor and metastasis suppressor in breast cancer.
- The immune mechanisms underlying LSD1's role in metastasis are not well understood.
Purpose of the Study:
- To investigate the role of natural killer (NK) cells in LSD1-mediated suppression of breast cancer metastasis.
- To elucidate the impact of LSD1 ablation on the tumor immune microenvironment and NK cell function.
- To identify mechanisms by which epigenetic alterations affect NK cell-mediated tumor surveillance.
Main Methods:
- Utilized the MMTV-PyMT breast cancer mouse model to study LSD1 function and NK cell involvement.
- Analyzed gene expression changes, focusing on immune-related genes like MHC-I, in tumor cells with and without LSD1.
- Performed transplantation experiments in SCID and NSG mice to assess the role of NK cells in metastasis.
- Investigated the effect of disrupting Qa-1 expression on NK cell cytotoxicity.
Main Results:
- Ablation of LSD1 in MMTV-PyMT tumors led to increased lung metastasis.
- LSD1 deficiency caused upregulation of MHC-I genes and altered the tumor immune microenvironment, reducing NK cell abundance and maturation.
- NK cells showed reduced cytotoxicity towards Lsd1-null tumor cells, which was partially restored by disrupting Qa-1 expression.
- Lsd1-null tumor cells formed larger metastatic lesions in NK cell-competent mice but not in NK cell-deficient mice.
Conclusions:
- Epigenetic deregulation of LSD1 in breast cancer cells impairs NK cell-mediated tumor surveillance.
- LSD1 deficiency reprograms the tumor immune microenvironment, enhancing metastatic progression.
- Targeting the Qa-1/CD94/NKG2A axis may represent a therapeutic strategy to restore NK cell function and control metastasis.
