Type I conventional dendritic cells facilitate immunotherapy in pancreatic cancer

Science, Journal Year: 2024, Volume and Issue: 384(6703)

Published: June 27, 2024

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 + T cell activation elimination of ptPDAC restoration life span even upon rechallenge. Using antigen-loaded cDC1s as a vaccine, immunotherapy-resistant was rendered sensitive iCBT tumors. cDC1 vaccination identified specific CDR3 sequences the tumor-infiltrating potential therapeutic importance. This study identifies fundamental difference immune microenvironment concurrent with, without, provides rationale for combining treatment option.

Language: Английский

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Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: July 3, 2020

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads respiratory failure, need for mechanical ventilation, and death. Most of the lung damage driven by surge in inflammatory cytokines [interleukin-6, interferon-γ, granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead improvement. GM-CSF produced many cells, including macrophages T-cells. GM-CSF-derived signals are involved differentiation macrophages, alveolar (AMs). In animal models infections, intranasal administration increased proliferation AMs improved outcomes. Increased levels have been recently described patients compared healthy controls. While might be beneficial some circumstances as an appropriate response, case response maladaptive virtue being later disproportionate. The inhibition signaling improving hyperinflammation-related most cases COVID-19. This blockade can achieved through antagonism receptor or direct binding circulating GM-CSF. Initial findings treated single intravenous dose mavrilimumab, monoclonal antibody α, showed oxygenation improvement shorter hospitalization. Prospective, randomized, placebo-controlled trials ongoing. Anti-GM-CSF antibodies, TJ003234 gimsilumab, will tested COVID-19, while lenzilumab received FDA approval compassionate use. These help inform whether blunting provided axis beneficial.

Language: Английский

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<p>GM-CSF: A Promising Target in Inflammation and Autoimmunity</p>

ImmunoTargets and Therapy, Journal Year: 2020, Volume and Issue: Volume 9, P. 225 - 240

Published: Oct. 1, 2020

Abstract: The cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), was firstly identified as being able to induce in vitro the proliferation and differentiation of bone marrow progenitors into granulocytes macrophages. Much preclinical data have indicated that GM-CSF has a wide range functions across different tissues its action on myeloid cells, deletion/depletion approaches indicate potential an important therapeutic target several inflammatory autoimmune disorders, for example, rheumatoid arthritis. In this review, we discuss briefly biology GM-CSF, raise some current issues questions pertaining biology, summarize results from models disorders list latest clinical trials evaluating blockade such disorders. Keywords: inflammation, autoimmunity,

Language: Английский

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Breast cancer–derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(20)

Published: Sept. 14, 2021

Tumor-infiltrating myeloid cells contribute to the development of immunosuppressive tumor microenvironment. Myeloid cell expression arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T function and depleting extracellular l-arginine, but mechanism underlying this expression, especially in breast cancer, is poorly understood. In cancer clinical samples our mouse models, we identified tumor-derived GM-CSF as primary regulator ARG1 local immune suppression through gene-KO screen cell-produced factors. The induction required low pH environment. signaling STAT3 p38 MAPK acid cAMP were activate STAT6-independent manner. Importantly, cell-derived promoted progression host antitumor immunity, driving significant accumulation ARG1-expressing compared with lung melanoma tumors minimal expression. Blockade tumoral enhanced efficacy tumor-specific adoptive therapy checkpoint blockade. Taken together, show that contributes microenvironment regulating can be targeted enhance immunotherapy.

Language: Английский

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Hydrogel-guided strategies to stimulate an effective immune response for vaccine-based cancer immunotherapy

Science Advances, Journal Year: 2022, Volume and Issue: 8(47)

Published: Nov. 23, 2022

Cancer vaccines have attracted widespread interest in tumor therapy because of the potential to induce an effective antitumor immune response. However, many challenges including weak immunogenicity, off-target effects, and immunosuppressive microenvironments prevented their broad clinical translation. To overcome these difficulties, delivery systems been designed for cancer vaccines. As carriers vaccine systems, hydrogels gained substantial attention they can encapsulate a variety antigens/immunomodulators protect them from degradation. This enables simultaneously reverse immunosuppression stimulate Meanwhile, controlled release properties allow precise temporal spatial loads situ further enhance response Therefore, this review summarizes classification vaccines, highlights strategies hydrogel-based provides some insights into future development

Language: Английский

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The role of lung macrophages in acute respiratory distress syndrome

Inflammation Research, Journal Year: 2022, Volume and Issue: 71(12), P. 1417 - 1432

Published: Oct. 20, 2022

Language: Английский

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Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: Aug. 1, 2022

The 2019 coronavirus disease (COVID-19) pandemic has become a global crisis. In the immunopathogenesis of COVID-19, SARS-CoV-2 infection induces an excessive inflammatory response in patients, causing cytokine storm severe cases. Cytokine leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is important cause COVID-19 progression even death. Among them, activation pathways major factor generating storms dysregulated immune responses, closely related severity viral infection. Therefore, elucidation signaling pathway providing otential therapeutic targets treatment strategies against COVID-19. Here, we discuss pathogenesis including induction, function, downstream signaling, as well existing potential interventions targeting these cytokines or pathways. We believe that comprehensive understanding regulatory dysregulation inflammation will help develop better clinical therapy effectively control diseases, such

Language: Английский

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COVID‐19 immunopathology: From acute diseases to chronic sequelae

Journal of Medical Virology, Journal Year: 2022, Volume and Issue: 95(1)

Published: Sept. 3, 2022

The clinical manifestation of coronavirus disease 2019 (COVID-19) mainly targets the lung as a primary affected organ, which is also critical site immune cell activation by severe acute respiratory syndrome 2 (SARS-CoV-2). However, recent reports suggest involvement extrapulmonary tissues in COVID-19 pathology. interplay both innate and adaptive responses key to management. As result, robust response provides first line defense, concomitantly, immunity neutralizes infection builds memory for long-term protection. dysregulated immunity, adaptive, can skew towards immunopathology chronic cases. Here we have summarized some findings that provide insight into caused SARS-CoV-2, post-acute Finally, further discuss immunomodulatory drugs preclinical trials dampening COVID-19.

Language: Английский

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Blocking GM-CSF receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers and neoangiogenesis in ex vivo cultured arteries from patients with giant cell arteritis

Annals of the Rheumatic Diseases, Journal Year: 2022, Volume and Issue: 81(4), P. 524 - 536

Published: Jan. 19, 2022

Effective and safe therapies are needed for the treatment of patients with giant cell arteritis (GCA). Emerging as a key cytokine in inflammation, granulocyte-macrophage colony stimulating factor (GM-CSF) may play role promoting inflammation GCA.

Language: Английский

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Understanding the development of Th2 cell-driven allergic airway disease in early life

Frontiers in Allergy, Journal Year: 2023, Volume and Issue: 3

Published: Jan. 10, 2023

Allergic diseases, including atopic dermatitis, allergic rhinitis, asthma, and food allergy, are caused by abnormal responses to relatively harmless foreign proteins called allergens found in pollen, fungal spores, house dust mites (HDM), animal dander, or certain foods. In particular, the activation of allergen-specific helper T cells towards a type 2 (Th2) phenotype during first encounters with allergen, also known as sensitization phase, is leading cause subsequent development disease. Infants children especially prone developing Th2 cell after initial contact allergens. But addition, rates diseases among increasing industrialized world have been associated living urban settings. Particularly for respiratory allergies, greater susceptibility has shown environments containing low levels microbial contaminants, principally bacterial endotoxins [lipopolysaccharide (LPS)], causative aeroallergens. This review highlights current understanding factors that balance immunity environmental allergens, particular focus on determinants program conventional dendritic (cDCs) toward away from stimulatory function. this context, it discusses transcription factor-guided functional specialization type-2 cDCs (cDC2s) how integration signals derived environment drives process. analyzes observational mechanistic studies supporting an essential role innate sensing microbial-derived products contained aeroallergens modulating immune responses. Finally, examines whether hyporesponsiveness stimulation, particularly LPS, risk factor induction infancy early childhood potential may affect early-age response LPS other components.

Language: Английский

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