Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma

Abstract

Mechanisms of immune regulation may control proliferation of aberrant plasma cells (PCs) in patients with monoclonal gammopathy of undetermined significance (MGUS) preventing progression to active multiple myeloma (MM). We hypothesized that CD85j (), an inhibitory immune checkpoint for B cell function, may play a role in MM pathogenesis. In this study, we report that patients with active MM had significantly lower levels of CD85j and its ligand S100A9. Decreased CD85j expression could also be detected in the premalignant condition MGUS, suggesting that loss of CD85j may be an early event promoting tumor immune escape. To gain insight into the molecular mechanisms underlying CD85j functions, we next enforced expression of CD85j in human myeloma cell lines by lentiviral transduction. Interestingly, gene expression profiling of CD85j-overexpressing cells revealed a set of downregulated genes with crucial functions in MM pathogenesis. Furthermore, in vitro functional assays demonstrated that CD85j overexpression increased susceptibility to T cell- and NK-mediated killing. Consistently, ligation of CD85j decreased the number of PCs from individuals with MGUS but not from patients with MM. In conclusion, downregulation of inhibitory immune checkpoints on malignant PCs may provide a novel mechanism of immune escape associated with myeloma pathogenesis.

Enhanced expression of FCER1G predicts positive prognosis in multiple myeloma

“…In the PPI network, many important genes that were associated with MM had been screened. S100A9 was reported significantly down-regulated in MM patients and further support MM survival by stimulating angiogenesis and cytokine secretion [33,34]. S100A9 was directly implicated in promoting Myeloid-derived suppressor cells (MDSC), which plays a critical role in the MM progression and can be considered as a therapeutic target in this disease [35].…”

Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy

“…Treatment with a LILRB1-blocking mAb (clone GHI/75) restored BiTE-mediated T cell activation (46). Intriguingly, previous studies have shown that LILRB1 loss in abnormal plasma cells may play a role in MM pathogenesis via a novel mechanism that allows early-stage malignancy to evade immune regulation (47)(48)(49). Lentiviral transduction was employed to force LILRB1 expression in human myeloma cell lines.…”

“…Subsequent gene expression profiling of LILRB1-overexpressing cells showed notable downregulation of key MM pathogenesis–related genes. Moreover, LILRB1 overexpression in MM cells increased susceptibility to both T and NK cell–mediated killing ( 47 ). Here, the loss of LILRB1 may confer a survival advantage for malignant plasma cells ( 47 ).…”

“…Moreover, LILRB1 overexpression in MM cells increased susceptibility to both T and NK cell–mediated killing ( 47 ). Here, the loss of LILRB1 may confer a survival advantage for malignant plasma cells ( 47 ). To date, research has focused on uncovering ways to antagonize LILRBs and reverse their inhibitory function to potentiate antitumor responses.…”

Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

“…Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells (PCs), resulting in increased monoclonal protein in the blood and urine ( 1 ). MM represents 1% of cancers and 13% of hematological malignancies, with a higher prevalence in aging populations ( 2 , 3 ). In 2019, approximately 3,300 Canadians were newly diagnosed with MM, and 1,550 Canadians died from this disease ( 4 ).…”