Butyrate Impedes the Recruitment of MDSCs to Alleviate CAC Development by Inhibition of the TLR2/MyD88/NF-κB Signaling Pathway

2021 ◽  
Author(s):  
Tengfei Xiao ◽  
Yi Chang ◽  
Hongmei Chen ◽  
Jingjing Kang ◽  
Mingzhong Sun
Keyword(s):  
Tumor Microenvironment ◽  
Mouse Model ◽  
Signaling Pathway ◽  
Immune Escape ◽  
Suppressor Cells ◽  
Short Chain Fatty Acids ◽  
Inhibitory Effect ◽  
Tumor Immune Escape ◽  
Tnf Α ◽  
Anal Prolapse

Abstract Background: The colitis-associated colorectal cancer (CAC) with inflammatory bowel disease (IBD) serving as its prelude often has a poor prognosis due to the hysteretic diagnosis. As a representative of short chain fatty acids (SCFAs), butyrate has been proved to have obvious antitumor effect. Here, we aimed to examine its effect on CAC and possible mechanism in tumor microenvironment (TME).Method: The establishment of CAC mouse model was mainly based on the combination of AOM intraperitoneal injection and DSS three cycle. HE staining was used to analyze the degree of colonic inflammation and tumor dysplasia. The proportion of MDSCs population was mainly evaluated by flow cytometry assay. RT-PCR, immunohistochemical staining and western blot analysis was carried out to detect protein molecular expression.Results: In our current study, the AOM-DSS induced CAC mouse model was utilized to evaluate the effect of butyrate on CAC. The administration of butyrate significantly improved the weight loss, falling survival rate, higher DAI index and anal prolapse caused by the AOM-DSS during the CAC modeling process. Anatomical results including the size and number of tumors and histological results including the abnormal hyperplasia shown by HE staining also confirmed the inhibitory effect of butyrate on CAC. In addition, the proportion of myeloid-derived suppressor cells (MDSCs) assisting tumor immune escape in tumor microenvironment (TME) decreased under the intervention of butyrate. And inflammatory mediators including CCL2, IL-6 and TNF-α in TME that induce the recruitment of MDSCs showed the same trend as MDSCs. Toll-like receptor 2 (TLR2) as a receptor molecule related to inflammation and immune function was also up-regulated in CAC, accompanied by the synchronous up-regulation of downstream Myd88 and NF-κB molecules, while the use of butyrate significantly inhibited the up-regulation of these molecules.Conclusions: Butyrate might reduce the release of CCL2, IL-6 and TNF-α in TME by inhibiting TLR2/MyD88/NF-κB signaling pathway to reduce the recruitment of MDSCs in TME, which eventually weakened the immune escape of tumors and retarded the progress of CAC.

scholarly journals Immunotherapy Targeting Myeloid-Derived Suppressor Cells (MDSCs) in Tumor Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Xidan Gao ◽  
Hongshu Sui ◽  
Shang Zhao ◽  
Xingmei Gao ◽  
Yanping Su ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Microenvironment ◽  
Immune Escape ◽  
Suppressor Cells ◽  
Tumor Immunotherapy ◽  
Therapeutic Effects ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Immune Escape ◽  
New Directions ◽  
Immature Myeloid Cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in tumor-bearing hosts to reduce T cells activity and promote tumor immune escape in the tumor microenvironment (TME). The immune system in the TME can be stimulated to elicit an anti-tumor immune response through immunotherapy. The main theory of immunotherapy resides on the plasticity of the immune system and its capacity to be re-educated into a potent anti-tumor response. Thus, MDSCs within the TME became one of the major targets to improve the efficacy of tumor immunotherapy, and therapeutic strategies for tumor MDSCs were developed in the last few years. In the article, we analyzed the function of tumor MDSCs and the regulatory mechanisms of agents targeting MDSCs in tumor immunotherapy, and reviewed their therapeutic effects in MDSCs within the TME. Those data focused on discussing how to promote the differentiation and maturation of MDSCs, reduce the accumulation and expansion of MDSCs, and inhibit the function, migration and recruitment of MDSCs, further preventing the growth, invasion and metastasis of tumor. Those investigations may provide new directions for cancer therapy.

scholarly journals Immunotherapy in Myeloproliferative Diseases

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1559 ◽  
Author(s):  
Lukas M. Braun ◽  
Robert Zeiser
Keyword(s):  
Bone Marrow ◽  
Immune Escape ◽  
Myeloproliferative Neoplasms ◽  
Suppressor Cells ◽  
Interferon Α ◽  
Tumor Immune Escape ◽  
Hematopoietic Stem ◽  
Myeloproliferative Diseases ◽  
Immunosuppressive Microenvironment ◽  
Inflammatory Milieu

Myeloproliferative diseases, including myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS), are driven by genetic abnormalities and increased inflammatory signaling and are at high risk to transform into acute myeloid leukemia (AML). Myeloid-derived suppressor cells were reported to enhance leukemia immune escape by suppressing an effective anti-tumor immune response. MPNs are a potentially immunogenic disease as shown by their response to interferon-α treatment and allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Novel immunotherapeutic approaches such as immune checkpoint inhibition, tumor vaccination, or cellular therapies using target-specific lymphocytes have so far not shown strong therapeutic efficacy. Potential reasons could be the pro-inflammatory and immunosuppressive microenvironment in the bone marrow of patients with MPN, driving tumor immune escape. In this review, we discuss the biology of MPNs with respect to the pro-inflammatory milieu in the bone marrow (BM) and potential immunotherapeutic approaches.

scholarly journals Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Xianjie Jiang ◽  
Jie Wang ◽  
Xiangying Deng ◽  
Fang Xiong ◽  
Junshang Ge ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Escape ◽  
Tumor Immune Escape

MMP-9-cleaved osteopontin isoform mediates tumor immune escape by inducing expansion of myeloid-derived suppressor cells

2017 ◽  
Vol 493 (4) ◽  
pp. 1478-1484 ◽  
Author(s):  
Lijuan Shao ◽  
Bo Zhang ◽  
Lingxiong Wang ◽  
Liangliang Wu ◽  
Quancheng Kan ◽  
...  
Keyword(s):  
Immune Escape ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Immune Escape

scholarly journals Vitamin D Blocks CLL Cell-Mediated MDSC Induction

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4355-4355
Author(s):  
Dimitrios Mougiakakos ◽  
Heiko Bruns ◽  
Martin Böttcher ◽  
Mirjeta Qorraj ◽  
Mario Fabri ◽  
...  
Keyword(s):  
Vitamin D ◽  
Immune Escape ◽  
Conflicts Of Interest ◽  
Suppressor Cells ◽  
Lymphocytic Leukemia ◽  
Bioactive Molecules ◽  
Tumor Immune Escape ◽  
Vitamin D Levels ◽  
Immune Defects ◽  
Lower Vitamin

Abstract Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence amongst adults. CLL-associated immune defects promote tumor immune escape and antagonize immune-based therapies. We and others have reported the accumulation of so-called myeloid-derived suppressor cells (MDSCs) in CLL. Accumulation of immunosuppressive CD14+HLA-DRlow monocytic MDSCs is associated with advanced disease and poor prognosis. The mechanisms re-polarizing CLL-monocytes remain unknown. Here, we describe that CLL-cell-derived exosomes elicit a phenotypical and functional skewing of regular monocytes towards MDSCs. However, pre-treating CLL-cells with vitamin D led to a loss of the exosomes' MDSC-promoting capability. In fact, higher vitamin 25D serum concentrations were linked to lower levels of circulating MDSCs in CLL. A plethora of bioactive molecules including microRNAs (miRs) is shuttled in exosomes. MiR-155 is found abundantly in CLL-exosomes and using antagomir against miR-155 prevented exosomal MDSC-induction. Furthermore, exosomes from patients with lower vitamin D levels contained more miR-155 copies. Accordingly, vitamin D application reduced miR-155 production in CLL-cells Overall, we identified that exosomal miR-155 transfer promotes MDSCs in CLL. Vitamin D interferes with this interplay and could thereby represent a mean for enhancing immune responses in CLL. Disclosures No relevant conflicts of interest to declare.

scholarly journals The role of tumor-derived exosomes in tumor immune escape: A concise review

2020 ◽  
Vol 7 (11) ◽  
pp. 4132-4137
Author(s):  
Nhat Chau Truong ◽  
Thao Nhi Huynh ◽  
Khuong Duy Pham ◽  
Phuc Van Pham
Keyword(s):  
Immune Modulation ◽  
Immune Escape ◽  
Suppressor Cells ◽  
Target Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Immune Escape ◽  
Concise Review ◽  
Viable Cells ◽  
Immune Escape Mechanisms

Exosomes are small vesicles secreted by viable cells into the microenvironment. These vesicles bring various compositions, including lipids, RNAs and proteins, which carry information from producer cells to target cells. Cancer cells also produce exosomes, termed as tumor-derived exosomes (TDEs), which play important roles in immune modulation, angiogenesis and metastasis of tumors. This review summarizes the roles of TDEs in tumor immune escape mechanisms. TDEs affect all kinds of tumor-associated immune cells, including natural killer (NK) cells, dendritic cells (DCs), T and B lymphocytes, and myeloid-derived suppressor cells (MDSCs). Generally, TDEs suppress the immune system to promote tumor immune escape, thereby significantly contributing to tumorigenesis and metastasis.

scholarly journals Inhibition of Arginase 1 Liberates Potent T Cell Immunostimulatory Activity of Human Neutrophil Granulocytes

2021 ◽  
Vol 11 ◽  
Author(s):  
Verena Vonwirth ◽  
Yagmur Bülbül ◽  
Anke Werner ◽  
Hakim Echchannaoui ◽  
Johannes Windschmitt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Escape ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Neutrophil Granulocytes ◽  
Tumor Immune Escape ◽  
Cell Functions ◽  
Arginase 1

Myeloid cell arginase-mediated arginine depletion with consecutive inhibition of T cell functions is a key component of tumor immune escape. Both, granulocytic myeloid-derived suppressor cells (G-MDSC) and conventional mature human polymorphonuclear neutrophil granulocytes (PMN) express high levels of arginase 1 and can act as suppressor cells of adaptive anti-cancer immunity. Here we demonstrate that pharmacological inhibition of PMN-derived arginase 1 not only prevents the suppression of T cell functions but rather leads to a strong hyperactivation of T cells. Human PMN were incubated in cell culture medium in the absence or presence of an arginase inhibitor. T cells from healthy donors were then activated either polyclonally or in an antigen-specific manner in the supernatants of the PMN cultures at different PMN-T cell ratios. T cell proliferation was completely suppressed in these supernatants in the absence of an arginase inhibitor. Arginase inhibition led to a strong hyperinduction of T cell proliferation, which exceeded control activation conditions up to 25-fold. The hyperinduction was correlated with higher PMN-T cell ratios and was only apparent when PMN arginase activity was blocked sufficiently. The T cell stimulatory factor was liberated very early by PMN and was present in the < 3 kDa fraction of the PMN supernatants. Increased T cell production of specific proinflammatory cytokines by PMN supernatant in the presence of arginase inhibitor was apparent. Upon arginase inhibition, downregulation of important T cell membrane activation and costimulation proteins was completely prevented or de novo induction accelerated. Antigen-specific T cell cytotoxicity against tumor cells was enhanced by PMN supernatant itself and could be further increased by PMN arginase blockade. Finally, we analyzed anergic T cells from multiple myeloma patients and noticed a complete reversal of anergy and the induction of strong proliferation upon T cell activation in PMN supernatants by arginase inhibition. In summary, we discovered a potent PMN-mediated hyperactivation of human T cells, which is apparent only when PMN arginase-mediated arginine depletion is concurrently inhibited. Our findings are clearly relevant for the analysis and prevention of human tumor immune escape in conjunction with the application of arginase inhibitors already being developed clinically.

scholarly journals EspH Suppresses Erk by Spatial Segregation from CD81 Tetraspanin Microdomains

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Rachana Pattani Ramachandran ◽  
Felipe Vences-Catalán ◽  
Dan Wiseman ◽  
Efrat Zlotkin-Rivkin ◽  
Eyal Shteyer ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Effector Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Human Pathogens ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
C Terminus ◽  
Tnf Α

ABSTRACT Enteropathogenic Escherichia coli (EPEC) belongs to a group of enteric human pathogens known as attaching-and-effacing (A/E) pathogens, which utilize a type III secretion system (T3SS) to translocate a battery of effector proteins from their own cytoplasm into host intestinal epithelial cells. Here we identified EspH to be an effector that prompts the recruitment of the tetraspanin CD81 to infection sites. EspH was also shown to be an effector that suppresses the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) signaling pathway at longer infection times. The inhibitory effect was abrogated upon deletion of the last 38 amino acids located at the C terminus of the protein. The efficacy of EspH-dependent Erk suppression was higher in CD81-deficient cells, suggesting that CD81 may act as a positive regulator of Erk, counteracting Erk suppression by EspH. EspH was found within CD81 microdomains soon after infection but was largely excluded from these domains at a later time. Based on our results, we propose a mechanism whereby CD81 is initially recruited to infection sites in response to EspH translocation. At a later stage, EspH moves out of the CD81 clusters to facilitate effective Erk inhibition. Moreover, EspH selectively inhibits the tumor necrosis factor alpha (TNF-α)-induced Erk signaling pathway. Since Erk and TNF-α have been implicated in innate immunity and cell survival, our studies suggest a novel mechanism by which EPEC suppresses these processes to promote its own colonization and survival in the infected gut.

scholarly journals Immunosuppressive Roles of Galectin-1 in the Tumor Microenvironment

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1398
Author(s):  
Yanyu Huang ◽  
Hsiao-Chi Wang ◽  
Junwei Zhao ◽  
Ming-Heng Wu ◽  
Tsung-Chieh Shih
Keyword(s):  
Tumor Microenvironment ◽  
Cell Function ◽  
Immune Cell ◽  
Immune Escape ◽  
Immune Surveillance ◽  
Human Tumor ◽  
Immune Cell Function ◽  
Tumor Immune Escape ◽  
Cancer Tumor ◽  
And Function

Evasion of immune surveillance is an accepted hallmark of tumor progression. The production of immune suppressive mediators by tumor cells is one of the major mechanisms of tumor immune escape. Galectin-1 (Gal-1), a pivotal immunosuppressive molecule, is expressed by many types of cancer. Tumor-secreted Gal-1 can bind to glycosylated receptors on immune cells and trigger the suppression of immune cell function in the tumor microenvironment, contributing to the immune evasion of tumors. The aim of this review is to summarize the current literature on the expression and function of Gal-1 in the human tumor microenvironment, as well as therapeutics targeting Gal-1.

scholarly journals Immunotherapy in tumors failing check-point inhibitors:the sarcoma example – What we missed and where we are heading

2017 ◽  
Vol 5 (2) ◽  
pp. 22-32
Author(s):  
Alessandra Merlini ◽  
Francesco Tolomeo ◽  
Sara Miano ◽  
Lorenzo D’Ambrosio ◽  
Dario Sangiolo ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Host Immune System ◽  
Tumor Immune Escape ◽  
Cancer Subtypes ◽  
Complex Interactions ◽  
Innate Immunity Cells ◽  
Antigen Presenting ◽  
Shed Light

The introduction of immune checkpoint inhibitors represented a true revolution in the treatment of melanoma and a few other cancer subtypes. Unfortunately, the use of these drugs did not achieve the same beneficial results in other neoplasms, such as soft tissue sarcoma and gastrointestinal stromal tumor. These failures encouraged deeper research into the complex interactions between cancer and host immune system, to try to shed light on the ability of cancer cells to escape immunologic surveillance. Key elements to explain tumor immune escape were found in the tumor microenvironment. The main actors in this complex network are lymphocytes, cytokines and innate immunity cells such as macrophages and antigen presenting cells. Thus, immuno-oncologists are studying the different components of the tumor microenvironment to identify possible new therapeutic targets. In this paper, we summarize the most important aspects of these interactions, and provide an overview of the newer and more promising immunotherapeutic strategies.

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