Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation

Li, Zhiqiang; Gu, Xin; Rao, Danni; Lü, Meiling; Wen, Jing; Chen, Xinyan; Wang, Hongbing; Cui, Xin; Tang, Wenwen; Xu, Shilin; Wang, Ping; Yu, Li

doi:10.1016/j.tranon.2021.101129

Cited by 13 publications

(7 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results were confirmed by other studies, showing that SEN177 treatment significantly enhanced ADCP by macrophages and neutrophil-mediated ADCC [ 232 , 233 , 234 ]. Another QPCTL inhibitor, luteolin, also abrogated the interaction between CD47 and SIRPα [ 235 ]. In addition, in co-cultures of H929 or DLD1 cancer cells with mouse bone-marrow-derived macrophages, phagocytosis was significantly improved after treatment with luteolin.…”

Section: Targeting Cd47-sirpα To Potentiate Antibody Therapymentioning

confidence: 99%

Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

Behrens

Berg

Egmond

2022

Cancers

View full text Add to dashboard Cite

In the past 25 years, a considerable number of therapeutic monoclonal antibodies (mAb) against a variety of tumor-associated antigens (TAA) have become available for the targeted treatment of hematologic and solid cancers. Such antibodies opsonize cancer cells and can trigger cytotoxic responses mediated by Fc-receptor expressing immune cells in the tumor microenvironment (TME). Although frequently ignored, neutrophils, which are abundantly present in the circulation and many cancers, have demonstrated to constitute bona fide effector cells for antibody-mediated tumor elimination in vivo. It has now also been established that neutrophils exert a unique mechanism of cytotoxicity towards antibody-opsonized tumor cells, known as trogoptosis, which involves Fc-receptor (FcR)-mediated trogocytosis of cancer cell plasma membrane leading to a lytic/necrotic type of cell death. However, neutrophils prominently express the myeloid inhibitory receptor SIRPα, which upon interaction with the ‘don’t eat me’ signal CD47 on cancer cells, limits cytotoxicity, forming a mechanism of resistance towards anti-cancer antibody therapeutics. In fact, tumor cells often overexpress CD47, thereby even more strongly restricting neutrophil-mediated tumor killing. Blocking the CD47-SIRPα interaction may therefore potentiate neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) towards cancer cells, and various inhibitors of the CD47-SIRPα axis are now in clinical studies. Here, we review the role of neutrophils in antibody therapy in cancer and their regulation by the CD47-SIRPα innate immune checkpoint. Moreover, initial results of CD47-SIRPα blockade in clinical trials are discussed.

show abstract

Section: Targeting Cd47-sirpα To Potentiate Antibody Therapymentioning

confidence: 99%

Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

Behrens

Berg

Egmond

2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Luteolin, a natural flavonoid compound, has potent anticancer effects in vitro and in vivo due to its natural antioxidant ability [170,171]. Luteolin has been verified as a novel inhibitor of isoQC by our lab; it directly interacts with isoQC protein, reduces pGlu modification of CD47 and its surface binding to SIRPa, and finally promotes macrophage-mediated phagocytosis [172]. Other natural compounds from microalgae have been synthesized to target QC or isoQC [173].…”

Section: Natural Products Targeting Qc/isoqcmentioning

confidence: 99%

Functions of glutaminyl cyclase and its isoform in diseases

Liu

Wang²

2023

Vis Cancer Med

Self Cite

View full text Add to dashboard Cite

Glutaminyl cyclase (QC; isoform: isoQC) is a zinc-dependent enzyme that catalyzes the intramolecular cyclization of N-terminal glutamine and glutamic acid residues into a pyroglutamate residue (pGlu). This conversion is a type of posttranslational modification called pyroglutamylation. The expression of QC/isoQC is regulated by epigenetics, cell homeostasis, and its substrates. Pyroglutamylation is an important maturation process during the synthesis and secretion of hormones, functioning in different diseases, such as Alzheimer’s disease, tumors, and other kinds of chronic diseases mediated by inflammation. IsoQC has been identified as a key regulator of the CD47-SIRPα checkpoint and is critical for the pyroglutamylation of CD47 at its SIRPα binding site, thus helping cancer cells evade immune surveillance. Inhibition of isoQC blocks the interaction between CD47 and SIRPα, leading to constrained tumor growth, indicating that isoQC is a novel target for immunotherapy. Targeting isoQC overcomes the side effects of targeting CD47 because isoQC is Golgi resident and is not expressed on erythrocytes. Small molecules and antibodies have been developed to target isoQC, and some of them have been tested in preclinical or clinical studies. Here, we briefly review the discovery history of QC/isoQC and then discuss its regulation and function in different diseases, emphasizing the unique role of isoQC in immunotherapy. Finally, we summarize the development of inhibitors and their progress in clinical trials with the hope of providing useful insights for future investigation of QC/isoQC and targeting it in various diseases.

show abstract

“…Li et al reported that luteolin can suppress the function of QPCTL, inhibiting the pGlu modification of CD47 and reducing its binding to SIRPα without affecting the translation and transcription of CD47. On the other hand, QPCTL is not expressed in erythrocytes, and anemia is avoided . Insilico Medicine and Fosun Pharmaceutical Co., Ltd. used the artificial intelligence platform to screen the first QPCTL small molecule inhibitor ISM004-1057D.…”

Section: Therapy Strategies Targeted On the Cd47-sirpα Axismentioning

confidence: 99%

“…On the other hand, QPCTL is not expressed in erythrocytes, and anemia is avoided. 70 Insilico Medicine and Fosun Pharmaceutical Co., Ltd. used the artificial intelligence platform to screen the first QPCTL small molecule inhibitor ISM004-1057D. Preclinical studies have shown that ISM004- To date, there have been some research advances in peptides targeting tumor cell CD47 (Table 2).…”

Section: Antibody and Fusion Proteinmentioning

confidence: 99%

Recent Advances of Tumor Therapy Based on the CD47-SIRPα Axis

et al. 2022

View full text Add to dashboard Cite

Cancer is still a major disease that is currently difficult for humans to overcome. When the expression of the cluster of differentiation 47 (CD47) is upregulated, tumor cells interact with the macrophage inhibitory receptor signal regulatory protein α (SIRPα) to transmit the "Don't eat me" signal, thereby avoiding phagocytosis by the macrophages. Therefore, when the CD47-SIRPα axis is inhibited, the macrophages' phagocytic function can be restored and can also exert antitumor effects. This Review mainly introduces recent advances in tumor therapy targeted on the CD47-SIRPα axis, including the antibody and fusion protein, small molecule, gene therapy, cell therapy, and drug delivery system, to inhibit the function of CD47 expressed on tumor cells and promote tumor phagocytosis by macrophages. In addition, this Review also summarizes the current approaches to avoid anemia, a common side effect of CD47-SIRPα inhibitions, and provides ideas for clinical transformation.

show abstract

Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation

Cited by 13 publications

References 30 publications

Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

Functions of glutaminyl cyclase and its isoform in diseases

Recent Advances of Tumor Therapy Based on the CD47-SIRPα Axis

Contact Info

Product

Resources

About