Abstract 364: Targeting LILRB1 to sensitize human myeloma to ferroptosis through disrupting cholesterol homeostasis

Abstract Multiple myeloma (MM) is a hematologic malignancy characterized by the uncontrolled clonal proliferation of plasma cells in the bone marrow (BM). Despite the demonstrated benefits of novel therapies, relapses are frequent, and acquired resistance to MM treatment eventually emerges in most, if not all, patients. MM patients who suffer more aggressive progression usually result in poorer survival. The genes driving such unfavored outcomes in MM have not been fully understood. Therefore, there is an urgent need to identify the genes and mechanisms that contribute to the aggressive behaviors of MM in order to develop improved therapeutic strategies for the disease. To discover new potential therapeutic targets for MM patients, we analyzed gene-profiling data of MM patients and identified leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, as one of the top-ranked genes associated with poor prognosis. LILRB1 on immune cells was reported to bind to its ligand, b2-microglobulin, on tumor cells. This interaction leads to immune suppression responses in various immune cells. However, the function of tumor-derived LILRB1 in tumor biology remains unclear and the role of LILRB1 in MM has been poorly studied. Our further analysis of the patient data demonstrated that MM patients with high expression of LILRB1 are closely related to higher MM recurrence rates, advanced stages, and lower survival rates, indicating that LILRB1 is an important player in MM pathogenesis and thus a promising target for MM therapy. Interestingly, RNA-seq data of human MM cells from the BM of MM-bearing mice showed that knockdown (KD) of LILRB1 activated cholesterol metabolism- and ferroptosis-related pathways in murine BM. Moreover, KD of LILRB1 significantly impaired tumor progression in murine models. Consistently, in vitro experiments also demonstrated that LILRB1 protected MM cells from ferroptosis inducer-caused lipid ROS and ferroptotic cell death, indicating that LILRB1 promotes the progression of MM cells by protecting them from ferroptosis. Further study were then conducted to reveal the underlying mechanism. LC-MS/MS analysis followed by co-IP demonstrated that LDLRAP1, an adaptor protein that interacts with LDLR, bound with LILRB1 and formed a complex together with LDLR. KD of LILRB1 inhibited LDL uptake by disrupting the interaction between LDLR and LDLRAP1 and triggering the compensatory cholesterol synthesis by upregulating the expression of SQLE that converted squalene to (S)-2,3-epoxysqualene. With less squalene to protect MM cells from lipid peroxidation, MM cells were more susceptible to the induction of ferroptosis. Thus, this study uncovers a novel function of LILRB1 in regulating cholesterol metabolism and protecting MM cells from ferroptosis during MM progression and implicates LILRB1 as a promising therapeutic target for MM patients. Citation Format: Miao Xian, Qing Yi, Qiang Wang, Liuling Xiao, Ling Zhong, chuanchao zhang, yabo Li, Jianfei Qian. Targeting LILRB1 to sensitize human myeloma to ferroptosis through disrupting cholesterol homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 364.