Abstract PR7: Epigenetic deregulation in LSD1-deficient luminal mammary tumor cells leads to their increased metastasis via reprogramming of the immune microenvironment

Abstract

Abstract It has become increasingly recognized that epigenetic deregulation makes significant contributions to metastasis. Mutations or deregulated expression of epigenetic regulators can alter expression of key cancer-related genes in tumor cells and may contribute to metastatic progression by affecting interaction of tumor cells with their immune microenvironment. LSD1 (KDM1A) is a histone demethylase that mainly serves as a transcriptional repressor by removing methyl groups from mono- and di-methylated lysine 4 on histone H3. In human breast cancer, LSD1 homozygous deletions and mutations are found in ~1-2% metastatic cases, suggesting that it may function as a metastasis suppressor. Consistent with this, in a mouse model of luminal breast cancer, MMTV-PyMT, we found that induced loss or inhibition of LSD1 led to a significant increase in lung metastasis. Characterization of the affected tumor cells showed a profound upregulation of many immune-related genes in LSD1-deficient cells, including genes for most MHC class I (MHC-I) (classical and non-classical) molecules, interferon and immune checkpoint pathways. FACS analysis revealed significant upregulation of the CD4+ T cell and monocytic myeloid-derived suppressor cell (MDSC) populations, and downregulation of CD8+ T-cell and NK-cell populations, in tumors with LSD1 deletion/inhibition. MHC-Is are ligands for inhibitory receptors on NK cells, and their interaction (e.g., interaction between a non-classical MHC-I, HLA-E [Qa-1 in mice] and CD94/NKG2A [on NK cells]) is a self-guarding mechanism to avoid killing of healthy “self” cells by NK cells. Upregulation of MHC-Is in Lsd1-null PyMT tumor cells may lead to suppression of NK cells. In fact, in a coculture system, NK cells exhibited reduced cytotoxicity toward Lsd1-null tumor cells. Under the in vivo setting, intraductal injection of PyMT tumor organoid cells to mammary glands of immunodeficient mice led to development of both primary tumors and lung metastasis; importantly, in NSG recipients (lack NK cells), both Lsd1-null and Lsd1-wild-type (wt) tumor cells formed lung metastatic lesions with similar sizes, whereas in SCID recipients (have NK cells), the sizes of metastatic lesions formed from Lsd1-wt tumor cells were significantly smaller than Lsd1-null cells. Collectively, these data suggest that epigenetic deregulation in LSD1-deficient luminal mammary tumor cells reprograms the tumor immune microenvironment, leading to reduced clearance of Lsd1-null PyMT tumor cells by NK cells, which may contribute to their increased metastasis. This study is not only important for understanding the immune mechanism underlying the metastasis-suppressive role of LSD1 in breast cancer, but also has important implications for immunotherapy: currently a strategy of combining checkpoint inhibitors with epigenetic drugs (e.g., LSD1 inhibitor) is being tested for improving immunotherapy; our study may help minimize the risk of (increased) metastasis potentially associated with this strategy. This abstract is also being presented as Poster B6. Citation Format: Dongxi Xiang, Zhe Li. Epigenetic deregulation in LSD1-deficient luminal mammary tumor cells leads to their increased metastasis via reprogramming of the immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR7.