scholarly journals N6-Methyladenosine RNA Modification: An Emerging Immunotherapeutic Approach to Turning Up Cold Tumors

2021 ◽  
Vol 9 ◽  
Author(s):  
Lei Zhan ◽  
Junhui Zhang ◽  
Suding Zhu ◽  
Xiaojing Liu ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Tumor Formation ◽  
Innate Immune ◽  
Rna Modification ◽  
Clinical Approach ◽  
Immunotherapeutic Approach ◽  
Different Types ◽  
Tumor Mutational Burden ◽  
And Function ◽  
Potential Use

Immunotherapy is a novel clinical approach that has shown clinical efficacy in multiple cancers. However, only a fraction of patients respond well to immunotherapy. Immuno-oncological studies have identified the type of tumors that are sensitive to immunotherapy, the so-called hot tumors, while unresponsive tumors, known as “cold tumors,” have the potential to turn into hot ones. Therefore, the mechanisms underlying cold tumor formation must be elucidated, and efforts should be made to turn cold tumors into hot tumors. N6-methyladenosine (m6A) RNA modification affects the maturation and function of immune cells by controlling mRNA immunogenicity and innate immune components in the tumor microenvironment (TME), suggesting its predominant role in the development of tumors and its potential use as a target to improve cancer immunotherapy. In this review, we first describe the TME, cold and hot tumors, and m6A RNA modification. Then, we focus on the role of m6A RNA modification in cold tumor formation and regulation. Finally, we discuss the potential clinical implications and immunotherapeutic approaches of m6A RNA modification in cancer patients. In conclusion, m6A RNA modification is involved in cold tumor formation by regulating immunity, tumor-cell-intrinsic pathways, soluble inhibitory mediators in the TME, increasing metabolic competition, and affecting the tumor mutational burden. Furthermore, m6A RNA modification regulators may potentially be used as diagnostic and prognostic biomarkers for different types of cancer. In addition, targeting m6A RNA modification may sensitize cancers to immunotherapy, making it a promising immunotherapeutic approach for turning cold tumors into hot ones.

scholarly journals The role of m6A modification in the biological functions and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiulin Jiang ◽  
Baiyang Liu ◽  
Zhi Nie ◽  
Lincan Duan ◽  
Qiuxia Xiong ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Modification ◽  
Biological Functions ◽  
Rna Methylation ◽  
Downstream Target ◽  
Different Types ◽  
M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

scholarly journals Role of the Inflammasome, IL-1β, and IL-18 in Bacterial Infections

2011 ◽  
Vol 11 ◽  
pp. 2037-2050 ◽  
Author(s):  
Manoranjan Sahoo ◽  
Ivonne Ceballos-Olvera ◽  
Laura del Barrio ◽  
Fabio Re
Keyword(s):  
Bacterial Infections ◽  
Innate Immune ◽  
Host Responses ◽  
Inflammasome Activation ◽  
Different Types ◽  
Molecular Aspects ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Receptor Family

The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1βand IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1βand IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future.

scholarly journals TLR7 modulating B-cell immune responses in the spleen of C57BL/6 mice infected with Schistosoma japonicum

2021 ◽  
Vol 15 (11) ◽  
pp. e0009943
Author(s):  
Haixia Wei ◽  
Hongyan Xie ◽  
Jiale Qu ◽  
Anqi Xie ◽  
Shihao Xie ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Gene Knockout ◽  
Innate Immune ◽  
Wild Type ◽  
Cell Responses ◽  
Splenic Cells ◽  
And Function ◽  
Egg Antigen

B cells played an important role in Schistosoma infection-induced diseases. TLR7 is an intracellular member of the innate immune receptor. The role of TLR7 on B cells mediated immune response is still unclear. Here, C57BL/6 mice were percutaneously infected by S. japonicum for 5–6 weeks. The percentages and numbers of B cells increased in the infected mice (p < 0.05), and many activation and function associated molecules were also changed on B cells. More splenic cells of the infected mice expressed TLR7, and B cells were served as the main cell population. Moreover, a lower level of soluble egg antigen (SEA) specific antibody and less activation associated molecules were found on the surface of splenic B cells from S. japonicum infected TLR7 gene knockout (TLR7 KO) mice compared to infected wild type (WT) mice (p < 0.05). Additionally, SEA showed a little higher ability in inducing the activation of B cells from naive WT mice than TLR7 KO mice (p < 0.05). Finally, the effects of TLR7 on B cells are dependent on the activation of NF-κB p65. Altogether, TLR7 was found modulating the splenic B cell responses in S. japonicum infected C57BL/6 mice.

Genome wide quantification of A-to-I RNA editing activity

2019 ◽  
Author(s):  
Shalom Hillel Roth ◽  
Erez Y. Levanon ◽  
Eli Eisenberg
Keyword(s):  
Rna Editing ◽  
Innate Immune ◽  
Rna Modification ◽  
Immune Disorders ◽  
Computational Tool ◽  
Genome Wide ◽  
Editing Activity ◽  
Single Number ◽  
Editing Level

Abstract Adenosine to inosine (A-to-I) RNA editing by the ADAR enzymes is a common RNA modification, preventing false activation of the innate immune system by endogenous dsRNAs. Methods for quantification of ADAR activity are sought after, due to an increasing interest in the role of ADARs in cancer and auto-immune disorders, as well as attempts to harness the ADAR enzymes for RNA engineering. Here we present the Alu Editing Index (AEI), a robust and simple-to-use computational tool devised for this purpose that produces a single number representing the global editing level from BAM files. The AEI tool is available at https://github.com/a2iEditing/RNAEditingIndexer

Substance and Function

2020 ◽  
pp. 188-203
Author(s):  
Jean-Pierre Llored
Keyword(s):  
Quantum Chemistry ◽  
Philosophy Of Science ◽  
Periodic Table ◽  
Functional Role ◽  
Functional Approach ◽  
Different Types ◽  
And Function

This paper aims to analyze the two aspects of elements, material and conceptual, in order to further understand the functional role played by elements in chemistry. First, we will refer to how Mendeleev gradually built his periodic table. Second, we will both highlight and reflect upon the functional role of elements in chemistry. In doing so, we will refer in particular to Cassirer’s philosophy of science. In conclusion, we propose that a functional approach is important for understanding current chemical practice, especially in nanochemistry and quantum chemistry. This approach also contributes to the analysis of different types of mereology that coexist in chemistry today.

Mitochondrial Quality Control and Restraining Innate Immunity

2020 ◽  
Vol 36 (1) ◽  
pp. 265-289
Author(s):  
Andrew T. Moehlman ◽  
Richard J. Youle
Keyword(s):  
Innate Immunity ◽  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Innate Immune ◽  
Interferon Response ◽  
Mitochondrial Quality Control ◽  
Selective Autophagy ◽  
Eukaryotic Organisms ◽  
And Function

Maintaining mitochondrial health is essential for the survival and function of eukaryotic organisms. Misfunctioning mitochondria activate stress-responsive pathways to restore mitochondrial network homeostasis, remove damaged or toxic proteins, and eliminate damaged organelles via selective autophagy of mitochondria, a process termed mitophagy. Failure of these quality control pathways is implicated in the pathogenesis of Parkinson's disease and other neurodegenerative diseases. Impairment of mitochondrial quality control has been demonstrated to activate innate immune pathways, including inflammasome-mediated signaling and the antiviral cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)–regulated interferon response. Immune system malfunction is a common hallmark in many neurodegenerative diseases; however, whether inflammation suppresses or exacerbates disease pathology is still unclear. The goal of this review is to provide a historical overview of the field, describe mechanisms of mitochondrial quality control, and highlight recent advances on the emerging role of mitochondria in innate immunity and inflammation.

Invariant NKT Cells Regulate Osteoclast Development and Function Under Homeostatic and during Conditions of Immune Activation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 104-104
Author(s):  
Ming Hu ◽  
J.H. Duncan Basssett ◽  
Lynette Danks ◽  
Emmanouil Spanoudakis ◽  
Ke Xu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nkt Cells ◽  
Innate Immune ◽  
Small Subset ◽  
Developmental Defect ◽  
Invariant Nkt Cells ◽  
And Function ◽  
Actin Rings

Abstract Invariant NKT cells, a small subset of immunoregulatory T cells restricted by the glycolipid-presenting non-polymorphic CD1d molecule, are able to modulate a variety of innate and adaptive immune responses. Osteoclasts (OC) are bone resorbing polykaryons of hematopoietic lineage, that have the capacity to regulate myeloid cell egress from bone marrow (BM) thus making them an integral part of the innate immune response. We and others previously showed that NKT cells regulate hematopoiesis in mice as well as humans. In this work, we investigate the role of NKT cells in OC development and function in homeostasis and after their specific activation by the model glycolipid alpha-galactosylceramide (aGC). Using quantitative back scattered electron scanning microscopy, we found that TCR Ja18 −/− mice which selectively lack development of NKT cells, exhibit a moderate osteopetrotic phenotype affecting trabecular as well as cortical bone. Histologically, these mice had the same number of TRAP+ OC as WT mice suggesting a maturation rather developmental defect in the TCR Ja18 −/−-derived OC. In vitro differentiation in the presence of RANKL and M-CSF showed that while TCR Ja18 −/− BM cells are capable of forming multinucleated OC, these, as assessed by confocal microscopy, fail to form F-actin rings and sealing zone and thus are unable to resorb bone. Further underscoring the effect of NKT cells in this process, CD45.1+ BM cells highly purified from CD45.2+ WT/CD45.1+ TCRJa18 −/− mixed BM chimeras displayed restoration of their OC F-actin rings. Next we investigated whether in vivo activated NKT cells regulate OC function. We found that a single injection of aGC dramatically increased the number of CD3-B220-CD11b-c-fmshighc- kithigh BM OC progenitors and accelerated the in vitro development of OC in WT but not TCR Ja18 −/− mice. Furthermore, this resulted in high serum levels of IFN-g and IL-4 but not IL-1 or IL-17. An aGC-mediated increase of OC progenitors was observed in IFN-g −/− but not IL-4 −/−mice suggesting that NKT cell-derived IL-4 is the main cytokine promoting osteoclastogenesis in this context. Taken together, our data demonstrate a novel role of NKT cells in homeostatic bone mass regulation and in the orchestration of innate immune responses through regulation of OC development and function.

scholarly journals Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies

2012 ◽  
Vol 30 (9) ◽  
pp. 1005-1014 ◽  
Author(s):  
Pasquale Sansone ◽  
Jacqueline Bromberg
Keyword(s):  
Interleukin 6 ◽  
Potential Role ◽  
Tumor Formation ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Metastatic Progression ◽  
And Function ◽  
Principal Pathway ◽  
Stat Pathway

The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers.

scholarly journals β-glucan-induced innate immune memory distinctively affects macrophage activation in response to differential environmental cues

2021 ◽  
Author(s):  
Alícia C. Piffer ◽  
Giorgio Camilli ◽  
Mathieu Bohm ◽  
Rachel Lavenir ◽  
Jessica Quintin
Keyword(s):  
Local Environment ◽  
Innate Immune ◽  
Immune Memory ◽  
Gm Csf ◽  
Different Types ◽  
And Function ◽  
Previous Encounter ◽  
Functional Phenotype

AbstractAdvances in the field of immunological memory demonstrate that innate immune cells can recall a previous encounter – the innate immune memory. In vitro, exposure of human primary monocytes to the fungal ²-glucan enhances their pro-inflammatory responsiveness towards several pathogens. During infection, circulating monocytes infiltrate tissues where, following conditioning by local environment, they differentiate and polarise into different types of macrophages. Hence in vivo interaction of β-glucan with innate cells would occur in a complex environment. Understanding the potential of β-glucan to induce innate immune memory in complex physiological environments is crucial for future translational research.Recapitulating different physiological conditions in vitro we found that β-glucan imprinting does not always enhance responsiveness and function of macrophages but can also reduce it. In this study, we show that upon both GM-CSF- and M-CSF-mediated polarisation, imprinting by β-glucan leads to less differentiated macrophages with a convergent functional phenotype. Altogether, these observations provide insightful and crucial knowledge that will help apprehending the in vivo high potential of β-glucan-induced innate memory in different pathological contexts.

Sign in / Sign up

Export Citation Format

Share Document