Myeloma-derived IL-32γ induced PD-L1 expression in macrophages facilitates immune escape via the PFKFB3-JAK1 axis

Liu, Yang; Yan, Haimeng; Gu, Huiyao; Zhang, Enfan; He, Jingsong; Cao, Wen; Qu, Jianwei; Xu, Rui‐hua; Cao, Liqin; He, Donghua; Zhang, Jinna; Hou, Yifan; Zhang, Cai

doi:10.1080/2162402x.2022.2057837

Cited by 21 publications

(13 citation statements)

References 35 publications

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“…The binding of PR3 to IL-32 was recently confirmed (Liu et al, 2021). Moreover, the involvement of these players was demonstrated in myeloma, in which secreted IL-32 g was shown to act via PR3 to enhance PDL-1 expression (Liu et al, 2022). PR3 is also known as Wegener's autoantigen and autoantibodies to PR3 are known as antineutrophil-cytoplasmic-autoantibodies (ANCA).…”

Section: Il-32 Binding Protein (2005)mentioning

confidence: 87%

Nine receptors and binding proteins, four drugs, and one woman: Historical and personal perspectives

Novick

2022

Front. Drug. Discov.

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In the era of bioinformatics and high-throughput techniques, it is tempting to forget the advantage of an old yet efficient and straightforward technique, ligand affinity chromatography, in the search for unknown proteins. This type of separation is based on an interaction between the target analyte potentially present in a crude mixture of proteins and a ligand coupled covalently to a resin. This process allows thousands-fold purification in a single step, which is crucial when using an extremely rich source of naturally occurring proteins such as human urine or plasma. Before the completion of The Genome Project, this method facilitated the rapid and reliable cloning of the corresponding gene based on the partial amino acid sequence of the isolated protein. Upon completion of this project, a partial protein sequence was enough to retrieve its complete mRNA and, hence, its complete protein sequence. Ligand affinity chromatography is indispensable for the isolation of both expected and unexpected binding proteins found by serendipity. My approach of combining a rich source of human proteins (1,000-fold concentrated human urine) together with this highly specific isolation method yielded proteins from both groups. The expected proteins included the two receptors for TNF (TBPI and TBPII), type I and type II interferon receptors (IFNα/βR, IFN-γR), and IL-6 and LDL receptors. The unexpected group of proteins included IL-18 binding protein (IL-18BP), IL-32 binding protein (Proteinase 3), and heparanase binding protein, the resistin. The discovery of the type I IFN receptor was a “eureka” moment in my life since it put an end to a 35-year worldwide search for this receptor. Using chemical purification methods, the TBPII might have never been discovered. Years later, TBPII was translated into the blockbuster drug Enbrel® to treat mainly rheumatoid arthritis. IFN-beta was translated into the blockbuster drug Rebif® to treat the autoimmune disease multiple sclerosis. IL-18BP translated into the drug Tadekinig alfa™ and is in a phase III clinical study for inflammatory and autoimmune pathologies. It has saved the lives of children born with mutations (NLRC4, XIAP) and is an example of personalized medicine. COVID-19 and CAR-T cytokine storms are the recent targets of IL-18BP.

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Section: Il-32 Binding Protein (2005)mentioning

confidence: 87%

Nine receptors and binding proteins, four drugs, and one woman: Historical and personal perspectives

Novick

2022

Front. Drug. Discov.

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“…In an early study, IL-32 was shown to promote the differentiation of monocytes into macrophages while the generation of functional dendritic cells was inhibited ( 39 ), which may suggest that IL-32 can have negative effects on immune responses. Indeed, more recently, myeloma-derived IL-32 was shown to promote the formation of immunosuppressive, M2-like macrophages ( 8 , 40 , 41 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is shown to be an important growth factor and metabolic regulator of MM cells ( 5 ). Furthermore, IL-32 is secreted by MM cells in exosomes and alters the tumor microenvironment by promoting osteoclastogenesis and bone degradation ( 6 ) as well as immune suppression ( 7 , 8 ). High expression of IL-32 at diagnosis is observed in 10-15% of patients and these individuals have inferior survival compared to non-expressors ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

IL-32 is induced by activation of toll-like receptors in multiple myeloma cells

et al. 2023

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Multiple myeloma (MM) is a hematological cancer characterized by accumulation of malignant plasma cells in the bone marrow. The patients are immune suppressed and suffer from recurrent and chronic infections. Interleukin-32 is a non-conventional, pro-inflammatory cytokine expressed in a subgroup of MM patients with a poor prognosis. IL-32 has also been shown to promote proliferation and survival of the cancer cells. Here we show that activation of toll-like receptors (TLRs) promotes expression of IL-32 in MM cells through NFκB activation. In patient-derived primary MM cells, IL-32 expression is positively associated with expression of TLRs. Furthermore, we found that several TLR genes are upregulated from diagnosis to relapse in individual patients, predominantly TLRs sensing bacterial components. Interestingly, upregulation of these TLRs coincides with an increase in IL-32. Taken together, these results support a role for IL-32 in microbial sensing in MM cells and suggest that infections can induce expression of this pro-tumorigenic cytokine in MM patients.

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“…The expression of PD-L1 is controlled by multiple mechanisms [69]. For example, cytokines, microRNAs, and noncoding Y RNA contained in exosomes have been shown to increase PD-L1 expression in immune cells [31,[70][71][72]. NDEs extracted from plasma or cerebrospinal uid of PD patients are shown to contain various pathogenic proteins [24,33,34,44,45].…”

Section: Discussionmentioning

confidence: 99%

Neuron-derived exosomes trigger a PD-L1-mediated broad suppression of T cells in Parkinson’s disease

Chen

et al. 2022

Preprint

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Background Adaptive immunity plays an important role in Parkinson’s disease (PD). Multiple lines of evidence indicate a significant decrease in peripheral T cells in PD patients. Although this suppression impacts both overall immune and neuroimmune response in Parkinson’s disease, there is currently no mechanistic explanation for this important phenomenon reported by many clinical studies. Methods The exosomes were isolated from culture media of cell lines overexpressing α-synuclein A53T mutant (A53T-syn), plasma of transgenic mouse expressing A53T-syn, and dopaminergic neuron-specific organoid derived from induced pluripotent stem cells of familial PD patients carrying A53T-syn mutation (termed neuron-derived exosomes or NDEs). Western blot was used to measure the expressions of exosome markers and transmission electron microscopy was used to confirm the morphology of purified exosomes. The CD4 + and CD8 + T cells were purified from mouse spleen using a negative selection method and the effects of NDEs on the cytokines production, activation, and proliferation of purified CD4 + and CD8 + T cells were assessed by flow cytometry. Purified naïve CD4 + T cells were used to examine the effects of NDEs on CD4 + T cell differentiation. Results Exosomes derived from all three sources suppressed IL-4 and INF-γ production by both purified CD4 + and CD8 + T cells and inhibited T cell activation and proliferation. The suppressed phenotype of T cells induced by NDEs was accompanied by a reduction of Th1-promoting transcription factor T-bet and Th2-promoting transcription factor GATA-3 in T cells. Consistently, NDEs isolated from plasma of A53T-syn mice and dopaminergic neuron-specific organoid carrying A53T-syn mutation also suppressed Th1 and Th2 differentiation of naïve CD4 + T cells. Mechanistically, the suppressed phenotype induced by NDEs isolated from PD models was associated with altered programmed death ligand 1 (PD-L1) level in T cells. Blocking PD-L1 with an anti-PD-L1 antibody or a small molecule inhibitor BMS-1166 reversed T cell suppression induced by A53T-syn exosomes. Conclusions Our study reveals the key role of neuron-derived exosomes in mediating the broad suppression of T cells observed in PD and provides the basis for exploring peripheral T cells in PD pathogenesis and as biomarkers or therapeutic targets for the disease.

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Myeloma-derived IL-32γ induced PD-L1 expression in macrophages facilitates immune escape via the PFKFB3-JAK1 axis

Cited by 21 publications

References 35 publications

Nine receptors and binding proteins, four drugs, and one woman: Historical and personal perspectives

Nine receptors and binding proteins, four drugs, and one woman: Historical and personal perspectives

IL-32 is induced by activation of toll-like receptors in multiple myeloma cells

Neuron-derived exosomes trigger a PD-L1-mediated broad suppression of T cells in Parkinson’s disease

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