Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils

Mahiddine, Karim; Blaisdell, Adam; Ma, Stephany; Créquer-Grandhomme, Amandine; Lowell, Clifford A.; Erlebacher, Adrian

doi:10.1172/jci130952

Cited by 81 publications

(74 citation statements)

References 62 publications

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“…Changes in the hypoxia-regulated molecular mechanisms are associated to contrasting properties of polymorphonuclear neutrophils (NTs) in different tumor settings [ 28 ]. Here, a decreased hepatic MPO activity was observed in DEN/TAA-treated mice in relation to untreated (healthy) animals ( Figure 1 F).…”

Section: Resultsmentioning

confidence: 99%

Chenopodium Quinoa and Salvia Hispanica Provide Immunonutritional Agonists to Ameliorate Hepatocarcinoma Severity under a High-Fat Diet

2020

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Complex interactions between immunonutritional agonist and high fat intake (HFD), the immune system and finally gut microbiota are important determinants of hepatocarcinoma (HCC) severity. The ability of immunonutritional agonists to modulate major aspects such as liver innate immunity and inflammation and alterations in major lipids profile as well as gut microbiota during HCC development is poorly understood. 1H NMR has been employed to assess imbalances in saturated fatty acids, MUFA and PUFA, which were associated to variations in iron homeostasis. These effects were dependent on the botanical nature (Chenopodium quinoa vs. Salvia hispanica L.) of the compounds. The results showed that immunonutritional agonists’ promoted resistance to hepatocarcinogenesis under pro-tumorigenic inflammation reflected, at a different extent, in increased proportions of F4/80+ cells in injured livers as well as positive trends of accumulated immune mediators (CD68/CD206 ratio) in intestinal tissue. Administration of all immunonutritional agonists caused similar variations of fecal microbiota, towards a lower obesity-inducing potential than animals only fed a HFD. Modulation of Firmicutes to Bacteroidetes contents restored the induction of microbial metabolites to improve epithelial barrier function, showing an association with liver saturated fatty acids and the MUFA and PUFA fractions. Collectively, these data provide novel findings supporting beneficial immunometabolic effects targeting hepatocarcinogenesis, influencing innate immunity within the gut-liver axis, and providing novel insights into their immunomodulatory activity.

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Section: Resultsmentioning

confidence: 99%

Chenopodium Quinoa and Salvia Hispanica Provide Immunonutritional Agonists to Ameliorate Hepatocarcinoma Severity under a High-Fat Diet

2020

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“…The mechanisms of anti-tumor functions of neutrophils are varied. Through the generation of ROS, such as H2O2, neutrophils were shown to be able to kill tumor cells in vitro and in tumor mouse models [ 136 ]. The production of ROS by neutrophils can also suppress the pro-tumorigenic role of the IL-17-secreting γδ T cells in tumors, which inhibits their proliferation [ 137 ].…”

Section: Neutrophilsmentioning

confidence: 99%

Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells

Domagala

Laplagne

Leveque

et al. 2021

Cancers

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Interactions between malignant cells and neighboring stromal and immune cells profoundly shape cancer progression. New forms of therapies targeting these cells have revolutionized the treatment of cancer. However, in order to specifically address each population, it was essential to identify and understand their individual roles in interaction between malignant cells, and the formation of the tumor microenvironment (TME). In this review, we focus on the myeloid cell compartment, a prominent, and heterogeneous group populating TME, which can initially exert an anti-tumoral effect, but with time actively participate in disease progression. Macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells, eosinophils, and basophils act alone or in concert to shape tumor cells resistance through cellular interaction and/or release of soluble factors favoring survival, proliferation, and migration of tumor cells, but also immune-escape and therapy resistance.

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“…The authors showed that early in tumor progression, PMNs help to clear cancer cells from the circulation, however, at later stages, tumor associated neutrophils (TANs) switch to a pro-tumor, immunosuppressive phenotype ( 7 , 55 ). One recent study demonstrated that PMNs exhibit pro-tumor attributes in a hypoxic tumor microenvironment, and oxygenation of the tumor induced these PMNs to revert to their tumor killing phenotype ( 126 ). As described in the section “Diversity of the PMN Response: Activation States or Subsets?”, immature T-cell-suppressive PMNs, called PMN-myeloid derived suppressor cells (PMN-MDSCs), are associated with the tumor-permissive PMN phenotype in cancer ( 54 ).…”

Section: Pmns Are Subverted In Cancermentioning

confidence: 99%

The Neutrophil: Constant Defender and First Responder

et al. 2020

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The role of polymorphonuclear neutrophils (PMNs) in biology is often recognized during pathogenesis associated with PMN hyper-or hypo-functionality in various disease states. However, in the vast majority of cases, PMNs contribute to resilience and tissue homeostasis, with continuous PMN-mediated actions required for the maintenance of health, particularly in mucosal tissues. PMNs are extraordinarily well-adapted to respond to and diminish the damaging effects of a vast repertoire of infectious agents and injurious processes that are encountered throughout life. The commensal biofilm, a symbiotic polymicrobial ecosystem that lines the mucosal surfaces, is the first line of defense against pathogenic strains that might otherwise dominate, and is therefore of critical importance for health. PMNs regularly interact with the commensal flora at the mucosal tissues in health and limit their growth without developing an overt inflammatory reaction to them. These PMNs exhibit what is called a para-inflammatory phenotype, and have reduced inflammatory output. When biofilm growth and makeup are disrupted (i.e., dysbiosis), clinical symptoms associated with acute and chronic inflammatory responses to these changes may include pain, erythema and swelling. However, in most cases, these responses indicate that the immune system is functioning properly to re-establish homeostasis and protect the status quo. Defects in this healthy everyday function occur as a result of PMN subversion by pathological microbial strains, genetic defects or crosstalk with other chronic inflammatory conditions, including cancer and rheumatic disease, and this can provide some avenues for therapeutic targeting of PMN function. In other cases, targeting PMN functions could worsen the disease state. Certain PMN-mediated responses to pathogens, for example Neutrophil Extracellular Traps (NETs), might lead to undesirable symptoms such as pain or swelling and tissue damage/fibrosis. Despite collateral damage, these PMN responses limit pathogen dissemination and more severe damage that would otherwise occur. New data suggests the existence of unique PMN subsets, commonly associated with functional diversification in response to particular inflammatory challenges. PMN-directed therapeutic approaches depend on a greater understanding of this diversity. Here we outline the current understanding of PMNs in health and disease, with an emphasis on the positive manifestations of tissue and organ-protective PMN-mediated inflammation.

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Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils

Cited by 81 publications

References 62 publications

Chenopodium Quinoa and Salvia Hispanica Provide Immunonutritional Agonists to Ameliorate Hepatocarcinoma Severity under a High-Fat Diet

Chenopodium Quinoa and Salvia Hispanica Provide Immunonutritional Agonists to Ameliorate Hepatocarcinoma Severity under a High-Fat Diet

Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells

The Neutrophil: Constant Defender and First Responder

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