New agents and regimens for diffuse large B cell lymphoma

Wang, Liang; Li, Lin Rong; Young, Ken H.

doi:10.1186/s13045-020-01011-z

Cited by 111 publications

(90 citation statements)

References 142 publications

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“…In full agreement, our results show that anti-insulin antibody responses are induced by polyvalent insulin complexes generated by chemical crosslinking via disulfide bonds and independent of any additional adjuvants. Sulfhydryl group-containing drugs are used as immunosuppressive medication (Azathioprine (Baranzini, 2013)), antilymphoma treatment (Alethine (Wang et al, 2020)) or acute bronchitis treatment (Erdosteine (Cazzola et al, 2010)). Strikingly, their use was reported to result in the development of anti-insulin autoantibodies (Uchigata et al, 1994;Karimi et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Antibodies control metabolism by regulating insulin homeostasis

Amendt

Allies

Nicolò

et al. 2021

Preprint

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Homeostasis of metabolism by hormone production is crucial to maintain physiological integrity and disbalance can cause severe metabolic disorders such as diabetes mellitus. Here, we show that antibodies recognizing insulin are key regulators of blood glucose and metabolism controlling insulin concentrations. In fact, antibody-deficient mice and immunodeficiency patients show sub-physiological blood glucose, which becomes normal after total IgG injection. We show that insulin-specific IgG antibodies found in the serum of wildtype mice or healthy individuals are responsible for this regulation. Interestingly, we identify two fractions of anti-insulin IgM which differ in their affinity to insulin. The low affinity IgM fraction (anti-insulin IgMlow) neutralizes insulin and leads to increased blood glucose while the high affinity IgM fraction (anti-insulin IgMhigh) protects insulin from neutralization by anti-insulin IgG thereby preventing blood glucose dysregulation. In contrast to anti-insulin IgMhigh, anti-insulin IgMlow binds to dsDNA suggesting that it is multi-specific. This multi-specificity mediates the formation of larger immune complexes containing insulin which results in increased uptake and degradation of insulin by macrophages in the presence of anti-insulin IgMlow as compared to anti-insulin IgMhigh. To demonstrate that high affinity anti-insulin IgM acts as protector of insulin and counteracts insulin neutralization by anti-insulin IgG, we expressed the variable regions of the same anti-insulin antibody as IgG or IgM. Strikingly, only the anti-insulin IgM regulated insulin function and prevented IgG-mediated neutralization of insulin and subsequent blood glucose dysregulation. Since anti-insulin IgMhigh is generated in the course of an immune response and affinity maturation, its protective role suggests that preventing autoimmune damage and maintaining physiological homeostasis requires adaptive tolerance mechanisms that generate protective IgM antibodies during memory responses.

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Section: Discussionmentioning

confidence: 99%

Antibodies control metabolism by regulating insulin homeostasis

Amendt

Allies

Nicolò

et al. 2021

Preprint

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“…We found that the expression level of PDL-1 in DLBCL tissue was significantly higher than in normal tissues but significantly lower than in cHL, which may explain why the efficacy of immunotherapy in DLBCL patients is not as good as that in cHL. Meanwhile, DLBCL patients with a higher expression level of PD-L1 seem to show a correlation with an increased resistance to frontline therapy but always related to prolonged PFS if treated with anti-PD-1 antibody (El Hussein et al, 2020;Wang L. et al, 2020). In line with this, cluster B which was associated with worse prognosis showed a higher expression level of CD274/PD-L1 than cluster A.…”

Section: Discussionmentioning

confidence: 70%

Comprehensive Characterization of Cachexia-Inducing Factors in Diffuse Large B-Cell Lymphoma Reveals a Molecular Subtype and a Prognosis-Related Signature

Kuang

Liu

et al. 2021

Front. Cell Dev. Biol.

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BackgroundCachexia is defined as an involuntary decrease in body weight, which can increase the risk of death in cancer patients and reduce the quality of life. Cachexia-inducing factors (CIFs) have been reported in colorectal cancer and pancreatic adenocarcinoma, but their value in diffuse large B-cell lymphoma (DLBCL) requires further genetic research.MethodsWe used gene expression data from Gene Expression Omnibus to evaluate the expression landscape of 25 known CIFs in DLBCL patients and compared them with normal lymphoma tissues from two cohorts [GSE56315 (n = 88) and GSE12195 (n = 136)]. The mutational status of CIFs were also evaluated in The Cancer Genome Atlas database. Based on the expression profiles of 25 CIFs, a single exploratory dataset which was merged by the datasets of GSE10846 (n = 420) and GSE31312 (n = 498) were divided into two molecular subtypes by using the method of consensus clustering. Immune microenvironment between different subtypes were assessed via single-sample gene set enrichment analysis and the CIBERSORT algorithm. The treatment response of commonly used chemotherapeutic drugs was predicted and gene set variation analysis was utilized to reveal the divergence in activated pathways for distinct subtypes. A risk signature was derived by univariate Cox regression and LASSO regression in the merged dataset (n = 882), and two independent cohorts [GSE87371 (n = 221) and GSE32918 (n = 244)] were used for validation, respectively.ResultsClustering analysis with CIFs further divided the cases into two molecular subtypes (cluster A and cluster B) associated with distinct prognosis, immunological landscape, chemosensitivity, and biological process. A risk-prognostic signature based on CCL2, CSF2, IL15, IL17A, IL4, TGFA, and TNFSF10 for DLBCL was developed, and significant differences in overall survival analysis were found between the low- and high-risk groups in the training dataset and another two independent validation datasets. Multivariate regression showed that the risk signature was an independently prognostic factor in contrast to other clinical characteristics.ConclusionThis study demonstrated that CIFs further contribute to the observed heterogeneity of DLBCL, and molecular classification and a risk signature based on CIFs are both promising tools for prognostic stratification, which may provide important clues for precision medicine and tumor-targeted therapy.

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“…Recently, advances in immunotherapy, especially checkpoint blockade, have resulted in clinical success in treatment of late-stage cancers [ 26 ]. As for unsatisfactory outcomes for those relapsed and refractory DLBCL patients, it needs more efforts to discover new therapy approaches, such as immunomodulatory drugs, immune checkpoint inhibitors, and so on [ 27 ]. The relationship analysis between CDH23 expression and immune cell infiltration showed that CDH23 had a negatively significant correlation with tumor purity.…”

Section: Discussionmentioning

confidence: 99%

Methylation silencing CDH23 is a poor prognostic marker in diffuse large B-cell lymphoma

Cao

Guo

Huang

et al. 2021

Aging

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Cadherin-23(CDH23) mediates homotypic and heterotypic cell-cell adhesions in cancer cells. However, the epigenetic regulation, the biological functions, the mechanisms and the prognostic value of CDH23 in diffuse large B-cell lymphoma (DLBCL) are still unclear. The Gene Expression Profiling Interactive Analysis (GEPIA) and the Gene Expression Omnibus (GEO) database were employed to analyze the CDH23 expression level in DLBCL. The correlation of CDH23 expression and methylation was analyzed by LinkedOmics database. The prognostic value was analyzed via GEPIA. Correlated genes, target kinase, target miRNA, target transcription factor and biological functions were identified by LinkedOmics and GeneMANIA database. The relationship between CDH23 and the immune cell infiltration was explored by the Tumor Immune Estimation Resource (TIMER). The expression of CDH23 was reduced by DNA methylation significantly in DLBCL tissue. Reduction of CDH23 represented poor outcome of DLBCL patients. Functional enrichment analysis showed that CDH23 mainly enriched in cancer cell growth, cell metastasis, cell adhesion, cell cycle, drug catabolic process, leukocyte mediated immunity and DNA repair by some cancer related kinases, miRNAs and transcription factors. These results indicated that methylated reduction of CDH23 represented poor outcome of DLBCL. CDH23 is associated with essential biological functions and key molecules in DLBCL. CDH23 may play crucial roles in DLBCL tumorigenesis. Our results lay a foundation for further investigation of the role of CDH23 in DLBCL tumorigenesis.

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New agents and regimens for diffuse large B cell lymphoma

Cited by 111 publications

References 142 publications

Antibodies control metabolism by regulating insulin homeostasis

Antibodies control metabolism by regulating insulin homeostasis

Comprehensive Characterization of Cachexia-Inducing Factors in Diffuse Large B-Cell Lymphoma Reveals a Molecular Subtype and a Prognosis-Related Signature

Methylation silencing CDH23 is a poor prognostic marker in diffuse large B-cell lymphoma

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