scholarly journals GM-CSF Nitration Is a New Driver of Myeloid Suppressor Cell Activity in Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Bianca Calì ◽  
Andrielly H. R. Agnellini ◽  
Chiara Cioccarelli ◽  
Ricardo Sanchez-Rodriguez ◽  
Andrea Predonzani ◽  
...  
Keyword(s):  
Nitrosative Stress ◽  
Immune Cell ◽  
Cell Activity ◽  
Suppressor Cell ◽  
Tryptophan Residue ◽  
Gm Csf ◽  
Myeloid Suppressor Cell ◽  
Cell Functions ◽  
Macrophage Colony ◽  
Colorectal Cancer Patients

Reactive oxygen species, including RNS, contribute to the control of multiple immune cell functions within the tumor microenvironment (TME). Tumor-infiltrating myeloid cells (TIMs) represent the archetype of tolerogenic cells that actively contribute to dismantle effective immunity against cancer. TIMs inhibit T cell functions and promote tumor progression by several mechanisms including the amplification of the oxidative/nitrosative stress within the TME. In tumors, TIM expansion and differentiation is regulated by the granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced by cancer and immune cells. Nevertheless, the role of GM-CSF in tumors has not yet been fully elucidated. In this study, we show that GM-CSF activity is significantly affected by RNS-triggered post-translational modifications. The nitration of a single tryptophan residue in the sequence of GM-CSF nourishes the expansion of highly immunosuppressive myeloid subsets in tumor-bearing hosts. Importantly, tumors from colorectal cancer patients express higher levels of nitrated tryptophan compared to non-neoplastic tissues. Collectively, our data identify a novel and selective target that can be exploited to remodel the TME and foster protective immunity against cancer.

Toll-like receptors stimulate human neutrophil function

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2660-2669 ◽  
Author(s):  
Fumitaka Hayashi ◽  
Terry K. Means ◽  
Andrew D. Luster
Keyword(s):  
Immune Cell ◽  
Germ Line ◽  
Quantitative Polymerase Chain Reaction ◽  
Neutrophil Function ◽  
Human Neutrophils ◽  
Toll Like Receptors ◽  
Gm Csf ◽  
Latex Beads ◽  
Macrophage Colony ◽  
And Function

Abstract The first immune cell to arrive at the site of infection is the neutrophil. Upon arrival, neutrophils quickly initiate microbicidal functions, including the production of antimicrobial products and proinflammatory cytokines that serve to contain infection. This allows the acquired immune system enough time to generate sterilizing immunity and memory. Neutrophils detect the presence of a pathogen through germ line-encoded receptors that recognize microbe-associated molecular patterns. In vertebrates, the best characterized of these receptors are Toll-like receptors (TLRs). We have determined the expression and function of TLRs in freshly isolated human neutrophils. Neutrophils expressed TLR1, 2, 4, 5, 6, 7, 8, 9, and 10—all the TLRs except TLR3. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment increased TLR2 and TLR9 expression levels. The agonists of all TLRs expressed in neutrophils triggered or primed cytokine release, superoxide generation, and L-selectin shedding, while inhibiting chemotaxis to interleukin-8 (IL-8) and increasing phagocytosis of opsonized latex beads. The response to the TLR9 agonist nonmethylated CpG-motif-containing DNA (CpG DNA) required GM-CSF pretreatment, which also enhanced the response to the other TLR agonists. Finally, using quantitative polymerase chain reaction (QPCR), we demonstrate a chemokine expression profile that suggests that TLR-stimulated neutrophils recruit innate, but not acquired, immune cells to sites of infection. (Blood. 2003;102:2660-2669)

scholarly journals Immunostimulatory Effects of Live Lactobacillus sakei K040706 on the CYP-Induced Immunosuppression Mouse Model

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3573
Author(s):  
Seo-Yeon Kim ◽  
Ji-Sun Shin ◽  
Kyung-Sook Chung ◽  
Hee-Soo Han ◽  
Hwi-Ho Lee ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Cell Activity ◽  
Lactobacillus Sakei ◽  
Gm Csf ◽  
Positive Effects ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Immunosuppressed Mice

Our previous studies have shown that heat-killed Lactobacillus sakei K040706 exerts immunostimulatory and anti-inflammatory activities in macrophages, cyclophosphamide (CYP)-treated mice, and dextran sulfate sodium–induced colitis mice. However, the immunostimulatory effects of live Lactobacillus sakei K040706 (live K040706) against CYP-induced immunosuppression and its underlying molecular mechanisms remain unknown. Therefore, we investigated the immunostimulatory effects of live K040706 (108 or 109 colony forming unit (CFU)/day, p.o.) in CYP-induced immunosuppressed mice. Oral administration of live K040706 prevented the CYP-induced decreases in body weight, thymus index, natural killer (NK) cell activity, T and B cell proliferation, and cytokine (interferon (IFN)-γ, interleukin (IL)-2, and IL-12) production. The administration of live K040706 also exerted positive effects on the gut microbiota of CYP-induced mice, resulting in a microbiota composition similar to that of normal mice. Moreover, live K040706 significantly enhanced IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in the splenocytes and Peyer’s patch (PP) cells of mice and increased bone marrow (BM) cell proliferation. Taken together, our data indicate that live K040706 may effectively accelerate recovery from CYP-induced immunosuppression, leading to activation of the immune system. Therefore, live K040706 may serve as a potential immunomodulatory agent against immunosuppression.

scholarly journals GM-CSF primes cardiac inflammation in a mouse model of Kawasaki disease

2016 ◽  
Vol 213 (10) ◽  
pp. 1983-1998 ◽  
Author(s):  
Angus T. Stock ◽  
Jacinta A. Hansen ◽  
Matthew A. Sleeman ◽  
Brent S. McKenzie ◽  
Ian P. Wicks
Keyword(s):  
Kawasaki Disease ◽  
Mouse Model ◽  
Immune Cell ◽  
Cardiac Fibroblasts ◽  
Developed Countries ◽  
Water Soluble ◽  
Cardiac Inflammation ◽  
Gm Csf ◽  
Cytokines And Chemokines ◽  
Macrophage Colony

Kawasaki disease (KD) is the leading cause of pediatric heart disease in developed countries. KD patients develop cardiac inflammation, characterized by an early infiltrate of neutrophils and monocytes that precipitates coronary arteritis. Although the early inflammatory processes are linked to cardiac pathology, the factors that regulate cardiac inflammation and immune cell recruitment to the heart remain obscure. In this study, using a mouse model of KD (induced by a cell wall Candida albicans water-soluble fraction [CAWS]), we identify an essential role for granulocyte/macrophage colony-stimulating factor (GM-CSF) in orchestrating these events. GM-CSF is rapidly produced by cardiac fibroblasts after CAWS challenge, precipitating cardiac inflammation. Mechanistically, GM-CSF acts upon the local macrophage compartment, driving the expression of inflammatory cytokines and chemokines, whereas therapeutically, GM-CSF blockade markedly reduces cardiac disease. Our findings describe a novel role for GM-CSF as an essential initiating cytokine in cardiac inflammation and implicate GM-CSF as a potential target for therapeutic intervention in KD.

Phase II trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 386-386 ◽  
Author(s):  
Robin Kate Kelley ◽  
Emily Mitchell ◽  
Spencer Behr ◽  
Jimmy Hwang ◽  
Bridget Keenan ◽  
...  
Keyword(s):  
Immune Cell ◽  
Progression Free Survival ◽  
Immune Effector ◽  
Effector Cells ◽  
Gm Csf ◽  
Phase 2 Trial ◽  
Best Response ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stage 1

386 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. GM-CSF modulates immune effector cells and has demonstrated safety and improved survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial aims to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Design: Simon’s 2-stage. Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior CPI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 Safety Cohort) or in cycles 1 and 2 (Stage 2). Endpoints: 1◦: Progression-free survival at 6 months (PFS6) with H0 25% vs. H1 50%. Key 2◦: Safety, overall response rate (ORR) and duration (DOR), OS, PD-L1 expression. Exploratory: PBMC and tumor immune cell profiles, tumor genotype, microsatellite (in)stability (MSI or MSS). Results: Accrual has completed with 27 patients (pts) enrolled 5/2016-6/2017: F/M 13/14; median age 61 (range 37-77); intrahepatic 19 (70%), extrahepatic 7 (26%), mixed 1 (4%) cholangiocarcinoma; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6). Adverse events (AE): Related grade(Gr) ≥3 AE occurred in 4/27 (15%) pts including immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 thrombocytopenia in 1 pt each. Gr≤2 irAE in ≥5% were: arthralgia (33%), dry eye/mouth (15%), hyperthyroid/thyroiditis (15%), hypothyroid (15%), neuropathy (11%), rash (11%), and adrenal insufficiency (7%). Steroids were required in 3/27 (11%) pts. Disposition: 19 pts removed for PD, 1 for Gr2 irAE; 7 pts remain active on treatment. Median time on treatment: 6 cycles (range 2-22+). Best response by RECIST 1.1: Partial response (PR) in 5/24 (21%) evaluable pts (1 MSI, 4 MSS); minor regression and ≥50% CA 19-9 decline in 2 additional MSS pts for 11+ and 16+ months. PBMC analyses show changes in expression of activating and inhibitory markers including PD-1 on various immune cell populations. Conclusions: PEM plus induction GM-CSF is safe and tolerable in ABC. Durable radiographic and tumor marker responses including MSS pts warrant further study. PFS6, OS, and correlative analyses are ongoing. Clinical trial information: NCT02703714.

scholarly journals Lifting the innate immune barriers to antitumor immunity

2020 ◽  
Vol 8 (1) ◽  
pp. e000695 ◽  
Author(s):  
Carla V Rothlin ◽  
Sourav Ghosh
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Immune System ◽  
T Cell ◽  
Time Course ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Innate Immune ◽  
Cell Functions

The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.

scholarly journals Granulocyte Macrophage Colony-Stimulating Factor

2001 ◽  
Vol 194 (7) ◽  
pp. 873-882 ◽  
Author(s):  
Jonathan L. McQualter ◽  
Rima Darwiche ◽  
Christine Ewing ◽  
Manabu Onuki ◽  
Thomas W. Kay ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cell ◽  
Specific Antigen ◽  
Demyelinating Diseases ◽  
Colony Stimulating Factor ◽  
Cns Inflammation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, can be induced by immunization with a number of myelin antigens. In particular, myelin oligodendrocyte glycoprotein, a central nervous system (CNS)-specific antigen expressed on the myelin surface, is able to induce a paralytic MS-like disease with extensive CNS inflammation and demyelination in several strains of animals. Although not well understood, the egress of immune cells into the CNS in EAE is governed by a complex interplay between pro and antiinflammatory cytokines and chemokines. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is considered to play a central role in maintaining chronic inflammation. The present study was designed to investigate the previously unexplored role of GM-CSF in autoimmune-mediated demyelination. GM-CSF−/− mice are resistant to EAE, display decreased antigen-specific proliferation of splenocytes, and fail to sustain immune cell infiltrates in the CNS, thus revealing key activities for GM-CSF in the development of inflammatory demyelinating lesions and control of migration and/or proliferation of leukocytes within the CNS. These results hold implications for the pathogenesis of inflammatory and demyelinating diseases and may provide the basis for more effective therapies for inflammatory diseases, and more specifically for multiple sclerosis.

Manipulation of dendritic cells for host defence against intracellular infections

2006 ◽  
Vol 34 (2) ◽  
pp. 283-286 ◽  
Author(s):  
S. McCormick ◽  
M. Santosuosso ◽  
X.Z. Zhang ◽  
Z. Xing
Keyword(s):  
Dendritic Cells ◽  
Immune Cell ◽  
Host Defence ◽  
Murine Bone Marrow ◽  
Gm Csf ◽  
Dc Vaccines ◽  
Macrophage Colony ◽  
Intracellular Infections

Dendritic cells (DCs) are an important innate immune cell type which is the bridge between innate and adaptive immunity. Mounting experimental evidence suggests that manipulating DCs represents a powerful means to enhance host defence against intracellular infectious diseases. We have developed several strategies to manipulate DCs either in vivo or in vitro for the purpose of enhancing the effect of vaccination or immunotherapeutics. In vivo delivery of transgene encoding GM-CSF (granulocyte/macrophage colony-stimulating factor), a DC-activating cytokine, increases the number and activation status of DCs at various tissue sites and enhances antimicrobial immune responses in murine models. Co-expression or co-delivery of GM-CSF gene transfer vector with an antimicrobial vaccine enhances microbial antigen-specific T-cell responses and immune protection. Murine bone marrow-derived DCs are being manipulated in vitro and exploited as a vaccine delivery system. Transduction of DCs with a virus-vectored tuberculosis vaccine is a powerful way to activate T-cells in vivo. Such genetically modified DC vaccines can be administered either parenterally or mucosally via the respiratory tract.

Sign in / Sign up

Export Citation Format

Share Document