LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs

Su, Mei-Tzu; Kumata, Sakiko; Endo, Shota; Okada, Yoshinori; Takai, Toshiyuki

doi:10.1080/2162402x.2022.2060907

Cited by 30 publications

(27 citation statements)

References 58 publications

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“…In support to the correlation between Gal-8 and MDSCs, strong interaction was also found between Gal-8 and LILRB4 ( Fig.2A ), a receptor driving MDSC functions [12, 15, 37, 38]. Immunofluorescent labeling of Gal-8 overexpressed in cells displayed cytoplasmic punctate-like distribution, as shown in Fig.2B .…”

Section: Resultssupporting

confidence: 66%

“…In support to the correlation between Gal-8 and MDSCs, strong interaction was also found between Gal-8 and LILRB4 (Fig. 2A), a receptor driving MDSC functions [12,15,37,38].…”

Section: Galectin-8 Binds Lilrb4 To Induce Mdsc Expansionsupporting

confidence: 65%

“…Consistent with potential myeloid regulating ability of Gal-8, LILRB4 was reported to induce tolerance of dendritic cells and expansion of MDSCs [13, 15]. Thus, we investigated the effect of Gal-8 on to MDSCs defined as CD11b+, CD33+ and HLA-DR-cells.…”

Section: Resultsmentioning

confidence: 80%

“…Beyond AML, LILRB4 was evidently related to poor prognosis in solid tumor [12]. Researchers discovered that LILRB4 plays an important role in promoting MDSC expansion and cancer progression [13][14][15], making LILRB4 a promising target for a variety of tumor types [16,17]. However, it is still unclear which ligand of LILRB4 may be involved in shaping the microenvironment of solid tumors, which is irrelevant to the functions of previously reported ligands or binding proteins such as APOE, CD166 and β-amyloid [13].…”

Section: Introductionmentioning

confidence: 99%

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Galectin-8 is a major ligand of LILRB4 prompting MDSC functions in the tumor microenvironment

Wang

Sun²,

Deng

et al. 2022

Preprint

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The LILRB4 myeloid receptor has been implicated in an immunosuppressive microenvironment, with specific antibodies under preclinical or clinical development for tumor immunotherapy. However, it remains largely unknown which natural ligand may trigger LILRB4 to expand myeloid derived suppressive cells (MDSC), and the relevant downstream signaling pathways are also under debate. Here we show that Galectin-8 is a high-affinity functional ligand of LILRB4, and its ligation induces MDSC by activating STAT3 as well as inhibiting NF-κB. Importantly, Galectin-8 but not APOE could induce MDSC, and both ligands bind LILRB4 in a non-competitive manner. Antibodies recognizing a defined epitope on LILRB4 could efficiently block Galectin-8 binding and neutralize its effects on MDSC induction and relevant signaling pathways. Galectin-8 expression promoted B16 tumor growth in mice, and knockout of LILRB4 attenuated tumor growth in this context. The LILRB4-specific Galectin-8 blocking antibody efficiently suppressed MDSC expansion and tumor growth in vivo. These results identify Galectin-8 as a functionally important ligand of LILRB4, highlighting the blockade of LILRB4-Galectin-8 interaction as a promising strategy for cancer immunotherapy.

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Section: Resultssupporting

confidence: 66%

“…In support to the correlation between Gal-8 and MDSCs, strong interaction was also found between Gal-8 and LILRB4 (Fig. 2A), a receptor driving MDSC functions [12,15,37,38].…”

Section: Galectin-8 Binds Lilrb4 To Induce Mdsc Expansionsupporting

confidence: 65%

Section: Resultsmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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Galectin-8 is a major ligand of LILRB4 prompting MDSC functions in the tumor microenvironment

Wang

Sun²,

Deng

et al. 2022

Preprint

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“…It promotes tumor immune clearance by transforming the surrounding non-senescent cells into senescent cells. In contrast, maladaptive senescence increases the number of senescent tumor cells to attract and activate myeloid derived suppressor cells (MDSCs) and M2 macrophages via SASP, impairing senescent tumor cell clearance and secreting pro-angiogenic substances to enhance vascularization ( 18 , 19 ). However, the role and mechanism of cellular senescence in the progression and TME formation of HBV-related HCC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Identification of cell senescence molecular subtypes in prediction of the prognosis and immunotherapy of hepatitis B virus-related hepatocellular carcinoma

Xue

Chen

et al. 2022

Front. Immunol.

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Hepatitis B virus (HBV)-infected hepatocellular carcinoma (HCC) has a high incidence and fatality rate worldwide, being among the most prevalent cancers. The growing body of data indicating cellular senescence (CS) to be a critical factor in hepatocarcinogenesis. The predictive value of CS in HBV-related HCC and its role in the immune microenvironment are unknown. To determine the cellular senescence profile of HBV-related HCC and its role in shaping the immune microenvironment, this study employed a rigorous evaluation of multiple datasets encompassing 793 HBV-related HCC samples. Two novel distinct CS subtypes were first identified by nonnegative matrix factorization, and we found that the senescence-activated subgroup had the worst prognosis and correlated with cancer progression. C1 and C2 were identified as the senescence-suppressed and senescence-activated subgroups. The immune microenvironment indicated that C2 exhibited a relatively low immune status, higher tumor purity, and lower immune scores and estimated scores, while the C1 subgroup possessed a better prognosis. The CS score signature based on five genes (CENPA, EZH2, G6PD, HDAC1, and PRPF19) was established using univariate Cox regression and the lasso method. ICGC-LIRI and GSE14520 cohorts were used to validate the reliability of the CS scoring system. In addition, we examined the association between the risk score and hallmark pathways through gene set variation analysis and gene set enrichment analysis. The results revealed a high CS score to be associated with the activation of cell senescence-related pathways. The CS score and other clinical features were combined to generate a CS dynamic nomogram with a better predictive capacity for OS at 1, 2, and 3 years than other clinical parameters. Our study demonstrated that cellular senescence patterns play a non-negligible role in shaping the characteristics of the immune microenvironment and profoundly affecting tumor prognosis. The results of this study will help predict patient prognosis more accurately and may assist in development of personalized immunotherapy for HBV-related HCC patients.

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Leukocyte immunoglobulin‐like receptor B4: A keystone in immune modulation and therapeutic target in cancer and beyond

Liu,

Yang

2024

Cancer Innovation

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Leukocyte immunoglobulin‐like receptor B4 (LILRB4) significantly impacts immune regulation and the pathogenesis and progression of various cancers. This review discusses LILRB4's structural attributes, expression patterns in immune cells, and molecular mechanisms in modulating immune responses. We describe the influence of LILRB4 on T cells, dendritic cells, NK cells, and macrophages, and its dual role in stimulating and suppressing immune activities. The review discusses the current research on LILRB4's involvement in acute myeloid leukemia, chronic lymphocytic leukemia, and solid tumors, such as colorectal cancer, pancreatic cancer, non‐small cell lung cancer, hepatocellular carcinoma, and extramedullary multiple myeloma. The review also describes LILRB4's role in autoimmune disorders, infectious diseases, and other conditions. We evaluate the recent advancements in targeting LILRB4 using monoclonal antibodies and peptide inhibitors and their therapeutic potential in cancer treatment. Together, these studies underscore the need for further research on LILRB4's interactions in the tumor microenvironment and highlight its importance as a therapeutic target in oncology and for future clinical innovations.

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LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs

Cited by 30 publications

References 58 publications

Galectin-8 is a major ligand of LILRB4 prompting MDSC functions in the tumor microenvironment

Galectin-8 is a major ligand of LILRB4 prompting MDSC functions in the tumor microenvironment

Identification of cell senescence molecular subtypes in prediction of the prognosis and immunotherapy of hepatitis B virus-related hepatocellular carcinoma

Leukocyte immunoglobulin‐like receptor B4: A keystone in immune modulation and therapeutic target in cancer and beyond

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