Sympathetic nervous tone limits the development of myeloid-derived suppressor cells

2020 ◽  
Vol 5 (51) ◽  
pp. eaay9368 ◽  
Author(s):  
James T. Nevin ◽  
Marmar Moussa ◽  
William L. Corwin ◽  
Ion I. Mandoiu ◽  
Pramod K. Srivastava
Keyword(s):  
Tumor Immunity ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Sympathetic Nerves ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Bearing ◽  
Adaptive Immune Cells ◽  
Promote Tumor Growth ◽  
Sympathetic Nervous ◽  
And Function

Sympathetic nerves that innervate lymphoid organs regulate immune development and function by releasing norepinephrine that is sensed by immune cells via their expression of adrenergic receptors. Here, we demonstrate that ablation of sympathetic nervous system (SNS) signaling suppresses tumor immunity, and we dissect the mechanism of such immune suppression. We report that disruption of the SNS in mice removes a critical α-adrenergic signal required for maturation of myeloid cells in normal and tumor-bearing mice. In tumor-bearing mice, disruption of the α-adrenergic signal leads to the accumulation of immature myeloid-derived suppressor cells (MDSCs) that suppress tumor immunity and promote tumor growth. Furthermore, we show that these SNS-responsive MDSCs drive expansion of regulatory T cells via secretion of the alarmin heterodimer S100A8/A9, thereby compounding their immunosuppressive activity. Our results describe a regulatory framework in which sympathetic tone controls the development of innate and adaptive immune cells and influences their activity in health and disease.

scholarly journals Myeloid-derived suppressor cells are bound and inhibited by anti-thymocyte globulin

2019 ◽  
Vol 25 (1) ◽  
pp. 46-59 ◽  
Author(s):  
Young Suk Lee ◽  
Eduardo Davila ◽  
Tianshu Zhang ◽  
Hugh P Milmoe ◽  
Stefanie N Vogel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Suppressor Cells ◽  
Arginase Activity ◽  
T Cell Proliferation ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Bearing ◽  
And Function

Myeloid-derived suppressor cells (MDSCs) inhibit T cell responses and are relevant to cancer, autoimmunity and transplant biology. Anti-thymocyte globulin (ATG) is a commonly used T cell depletion agent, yet the effect of ATG on MDSCs has not been investigated. MDSCs were generated in Lewis Lung Carcinoma 1 tumor-bearing mice. MDSC development and function were assessed in vivo and in vitro with and without ATG administration. T cell suppression assays, RT-PCR, flow cytometry and arginase activity assays were used to assess MDSC phenotype and function. MDSCs increased dramatically in tumor-bearing mice and the majority of splenic MDSCs were of the polymorphonuclear subset. MDSCs potently suppressed T cell proliferation. ATG-treated mice developed 50% fewer MDSCs and these MDSCs were significantly less suppressive of T cell proliferation. In vitro, ATG directly bound 99.6% of MDSCs. CCR7, L-selectin and LFA-1 were expressed by both T cells and MDSCs, and binding of LFA-1 was inhibited by ATG pre-treatment. Arg-1 and PD-L1 transcript expression were reduced 30–40% and arginase activity decreased in ATG-pretreated MDSCs. MDSCs were bound and functionally inhibited by ATG. T cells and MDSCs expressed common Ags which were also targets of ATG. ATG may be helpful in tumor models seeking to suppress MDSCs. Alternatively, ATG may inadvertently inhibit important T cell regulatory events in autoimmunity and transplantation.

Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5457-5466 ◽  
Author(s):  
Yasushi Sawanobori ◽  
Satoshi Ueha ◽  
Makoto Kurachi ◽  
Takeshi Shimaoka ◽  
James E. Talmadge ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Bearing ◽  
Promote Tumor Growth ◽  
Brdu Labeling ◽  
And Migration ◽  
Stimulating Factor

Abstract Tumor growth is associated with aberrant myelopoiesis, including the accumulation of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) that have the potential to promote tumor growth. However, the identity, growth, and migration of tumor-associated MDSCs remain undefined. We demonstrate herein that MDSCs at tumor site were composed primarily of bone marrow-derived CD11b+Gr-1hiLy-6Cint neutrophils and CD11b+Gr-1int/dullLy-6Chi macrophages. Unexpectedly, in vivo bromodeoxyuridine (BrdU) labeling and parabiosis experiments revealed that tumor-infiltrating macrophages were replenished more rapidly than neutrophils. CCR2 deficiency caused striking conversion of infiltrating cellular dominance from macrophages to neutrophils in the tumor with the excessive production of CXCR2 ligands and granulocyte-colony stimulating factor in the tumor without affecting tumor growth. Overall, our data established the identity and dynamics of MDSCs in a tumor-bearing host mediated by chemokines and elucidated unexpected effects of the paucity of macrophages on tumor development.

scholarly journals Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Fengqian Chen ◽  
Jingquan Li ◽  
Hui Wang ◽  
Qian Ba
Keyword(s):  
Dendritic Cells ◽  
Chinese Medicine ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Traditional Chinese Medicine ◽  
Tumor Cells ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Adaptive Immune Cells

As the main cause of death in the world, cancer is one of the major health threats for humans. In recent years, traditional Chinese medicine has gained great attention in oncology due to the features of multi-targets, multi-pathways, and slight side effects. Moreover, lots of traditional Chinese medicine can exert immunomodulatory effects in vivo. In the tumor microenvironment, tumor cells, immune cells as well as other stromal cells often coexist. With the development of cancer, tumor cells proliferate uncontrollably, metastasize aggressively, and modulate the proportion and status of immune cells to debilitate the antitumor immunity. Reversal of immunosuppressive tumor microenvironment plays an essential role in cancer prevention and therapy. Immunotherapy has become the most promising strategy for cancer therapy. Chinese medicine compounds can stimulate the activation and function of immune cells, such as promoting the maturation of dendritic cells and inducing the differentiation of myeloid-derived suppressor cells to dendritic cells and macrophages. In the present review, we summarize and discuss the effects of Chinese medicine compounds on immune cells in the tumor microenvironment, including innate immune cells (dendritic cells, natural killer cells, macrophages, and myeloid-derived suppressor cells) and adaptive immune cells (CD4+/CD8+ T lymphocytes and regulatory T cells), and the various immunomodulatory roles of Chinese medicine compounds in cancer therapy such as improving tumor-derived inflammation, enhancing the immunity after surgery or chemotherapy, blocking the immune checkpoints, et al., aiming to provide more thoughts for the anti-tumor mechanisms and applications of Chinese medicine compounds in terms of tumor immunity.

scholarly journals 2363 Inducing anti-tumor immunity in colorectal cancer

2018 ◽  
Vol 2 (S1) ◽  
pp. 15-16
Author(s):  
Jonathan B. Mitchem ◽  
Yue Guan ◽  
Mark Daniels ◽  
Emma Teixeiro
Keyword(s):  
Colorectal Cancer ◽  
Statistical Analysis ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
Suppressor Cells ◽  
The United States ◽  
Cytotoxic T Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Bearing

OBJECTIVES/SPECIFIC AIMS: Despite significant advances in screening and treatment, colorectal cancer is the second leading cancer killer in the United States today. Some of the most promising recent developments in cancer therapy have come from immune-based therapy. Immune-based therapy, however, has shown limited utility in patients with colorectal cancer. Studies have previously shown that certain chemotherapy regimens may be more effective in combination with immune-based therapy due to induction of inflammation in the tumor microenvironment. In this study, we sought to determine how standard chemotherapy (FOLFOX) affects the generation of antigen-specific anti-tumor immunity in colorectal cancer. METHODS/STUDY POPULATION: To determine the how antigen-specific immunity and T cell responses are affected by FOLFOX, we utilized a model antigen expressing murine colon cancer cell line syngeneic to C57BL/6 (MC38-CEA). Treatment was initiated when tumor size reached 50 mm2. Mice were treated with either vehicle (PBS), 5-Fluorouracil (5-FU), Oxaliplatin, or combination (FOLFOX). Antigen-specific cytotoxic T cell (tet+Tc) were detected using Db-CEA-tetramer obtained from the NIH-tetramer core facility. Flow cytometry was performed for phenotypic analysis and tetramer positivity. Tumor growth was measured using standard caliper measurements. Statistical analysis was performed using t-test for continuous variables and ANOVA was used when comparing multiple groups. Statistical analysis was performed using SPSS. All arms were completed with n=3–7. RESULTS/ANTICIPATED RESULTS: To determine how systemic treatment with chemotherapy affects cytotoxic T cell development (Tc), we established that we could detect antigen-specific Tc (tet+Tc) in the spleen, tumor, and draining lymph nodes of tumor-bearing mice. After establishing that the system worked appropriately, tumor-bearing mice were treated with different chemotherapy regimens and tumor growth was monitored. As expected, the combination of FOLFOX was significantly better than either drug individually (2-way ANOVA, p<0.01). FOLFOX therapy also showed a significant (p<0.05) increase in the number of tumor-associated tet+Tc, and tet+Tc expressing phenotypic markers of effector (Te) and resident memory (Trm) subsets. Tumor-associated tet+Tc highly expressed PD-1 (>50%); however, this was not significantly different between treatment or vehicle arms. Since 5-FU, one component of FOLFOX has previously shown a selective reduction of myeloid-derived suppressor cells, we also investigated the myeloid compartment. There were no significant differences in conventional or plasmacytoid dendritic cells, myeloid-derived suppressor cells, or tumor-associated macrophages. DISCUSSION/SIGNIFICANCE OF IMPACT: The future of cancer care involves multi-modality care tailored to patients. To more effectively combine therapy it is critical that we understand how currently utilized therapy works. In this study, we show that the primary chemotherapy regimen utilized in colorectal cancer increases tumor-associated antigen-specific cytotoxic T cells and the majority of these cells are PD-1 positive. This suggests that FOLFOX may work in concert with immune-based therapy when selected appropriately. Further study is warranted to determine optimal combination therapy and ways to maximize anti-tumor immunity in order to improve the treatment of patients with this deadly disease.

scholarly journals Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1170
Author(s):  
Mithunah Krishnamoorthy ◽  
Lara Gerhardt ◽  
Saman Maleki Maleki Vareki
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Cancer Progression ◽  
Suppressor Cells ◽  
T Cell Immunity ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Immunity ◽  
Promote Tumor Growth

The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.

scholarly journals The Enigma of Low-Density Granulocytes in Humans: Complexities in the Characterization and Function of LDGs during Disease

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1091
Author(s):  
Brittany G. Seman ◽  
Cory M. Robinson
Keyword(s):  
Immune Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Low Density ◽  
Myeloid Derived Suppressor Cells ◽  
Disease States ◽  
Isolation Techniques ◽  
Microbial Infections ◽  
And Function

Low-density granulocytes (LDGs) have been characterized as important immune cells during healthy and disease states in humans, including microbial infections, cancer, and autoimmune dysfunction. However, the classification of this cell type is similar to other immune cells (e.g., neutrophils, myeloid-derived suppressor cells) and ambiguous functional standards have rendered LDG identification and isolation daunting. Furthermore, most research involving LDGs has mainly focused on adult cells and subjects, leaving increased uncertainty surrounding younger populations, especially in vulnerable neonatal groups where LDG numbers are elevated. This review aims to bring together the current research in the field of LDG biology in the context of immunity to disease, with a focus on infection. In addition, we propose to highlight the gaps in the field that, if filled, could improve upon isolation techniques and functional characterizations for LDGs separate from neutrophils and myeloid-derived suppressor cells (MDSCs). This will not only enhance understanding of LDGs during disease processes and how they differ from other cell types but will also aid in the interpretation of comparative studies and results with the potential to inform development of novel therapeutics to improve disease states in patients.

scholarly journals Down-regulation of PLCγ2–β-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer

2013 ◽  
Vol 210 (11) ◽  
pp. 2257-2271 ◽  
Author(s):  
Aude-Hélène Capietto ◽  
Seokho Kim ◽  
Dominic E. Sanford ◽  
David C. Linehan ◽  
Masaki Hikida ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Down Regulation ◽  
Tumor Bearing ◽  
Promote Tumor Growth ◽  
Negative Role ◽  
Cell Inhibition

Myeloid-derived suppressor cells (MDSCs) favor tumor promotion, mainly by suppressing antitumor T cell responses in many cancers. Although the mechanism of T cell inhibition is established, the pathways leading to MDSC accumulation in bone marrow and secondary lymphoid organs of tumor-bearing hosts remain unclear. We demonstrate that down-regulation of PLCγ2 signaling in MDSCs is responsible for their aberrant expansion during tumor progression. PLCγ2−/− MDSCs show stronger immune-suppressive activity against CD8+ T cells than WT MDSCs and potently promote tumor growth when adoptively transferred into WT mice. Mechanistically, PLCγ2−/− MDSCs display reduced β-catenin levels, and restoration of β-catenin expression decreases their expansion and tumor growth. Consistent with a negative role for β-catenin in MDSCs, its deletion in the myeloid population leads to MDSC accumulation and supports tumor progression, whereas expression of β-catenin constitutively active reduces MDSC numbers and protects from tumor growth. Further emphasizing the clinical relevance of these findings, MDSCs isolated from pancreatic cancer patients show reduced p-PLCγ2 and β-catenin levels compared with healthy controls, similar to tumor-bearing mice. Thus, for the first time, we demonstrate that down-regulation of PLCγ2–β-catenin pathway occurs in mice and humans and leads to MDSC-mediated tumor expansion, raising concerns about the efficacy of systemic β-catenin blockade as anti-cancer therapy.

scholarly journals The Role of Myeloid-Derived Suppressor Cells (MDSCs) in the Development and/or Progression of Endometriosis-State of the Art

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 677
Author(s):  
Dorota Suszczyk ◽  
Wiktoria Skiba ◽  
Joanna Jakubowicz-Gil ◽  
Jan Kotarski ◽  
Iwona Wertel
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Chronic Inflammation ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Immunological Diseases ◽  
Underlying Mechanisms ◽  
And Function ◽  
The Impact

Endometriosis (EMS) is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus. Approximately 10% of women around the world suffer from this disease. Recent studies suggest that endometriosis has potential to transform into endometriosis-associated ovarian cancer (EAOC). Endometriosis is connected with chronic inflammation and changes in the phenotype, activity, and function of immune cells. The underlying mechanisms include quantitative and functional disturbances of neutrophils, monocytes/macrophages (MO/MA), natural killer cells (NK), and T cells. A few reports have shown that immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) may promote the progression of endometriosis. MDSCs are a heterogeneous population of immature myeloid cells (dendritic cells, granulocytes, and MO/MA precursors), which play an important role in the development of immunological diseases such as chronic inflammation and cancer. The presence of MDSCs in pathological conditions correlates with immunosuppression, angiogenesis, or release of growth factors and cytokines, which promote progression of these diseases. In this paper, we review the impact of MDSCs on different populations of immune cells, focusing on their immunosuppressive role in the immune system, which may be related with the pathogenesis and/or progression of endometriosis and its transformation into ovarian cancer.

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