Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory-driven disease mouse models, we show that ...grapefruit-derived nanovectors (GNV) coated with inflammatory-related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of dextran sulfate sodium-induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that chemokines are overexpressed in diseased human tissue provides the rationale for using IGNVs to more directly deliver therapeutic agents to inflammatory tumor sites and the rationale for the use of IGNVs as treatment for certain cancers in personalized medicine.
Previous studies demonstrated that IL-12-driven antitumor activity is short-circuited by a rapid switch in dendritic cell (DC) function from immunogenic to tolerogenic activity. This process was ...dependent on IFN-γ and the tolerogenic phenotype was conferred by IDO. Extended monitoring of IDO(+) DC in the tumor-draining lymph nodes of IL-12 plus GM-CSF-treated tumor-bearing mice revealed that whereas IFN-γ induction was transient, IDO expression in DC was maintained long-term. An in vitro system modeling the IFN-γ-mediated change in DC function was developed to dissect the molecular basis of persistent IDO expression in post-IL-12 DC. Stimulation of DC with IFN-γ and CD40L resulted in rapid induction of IDO1 and IDO2 transcription and recapitulated the in vivo switch from immunogenic to tolerogenic activity. Long-term maintenance of IDO expression was found to be independent of exogenous and autocrine IFN-γ, or the secondary cytokines TGF-β, TNF-α, and IL-6. In contrast, both IDO enzymatic activity and IFN-γ-induced AhR expression were required for continued IDO transcription in vitro and in vivo. Addition of the tryptophan catabolite kynurenine to DC cultures in which IDO activity was blocked restored long-term IDO expression in wild-type DC but not in AhR-deficient DC, establishing the central role of the kynurenine-AhR pathway in maintaining IDO expression in tolerogenic DC. These findings shed further light on the cellular and molecular biology of the post-IL-12 regulatory rebound and provide insight into how feedback inhibitory mechanisms dominate in the long-term.
It is clear that obesity increases the risk of many types of cancer, including breast cancer. However, the underlying molecular mechanisms by which obesity is linked to cancer risk remain to be ...defined. Herein, we report that circulating adipose fatty acid binding protein (A-FABP) promotes obesity-associated breast cancer development. Using clinical samples, we demonstrated that circulating A-FABP levels were significantly increased in obese patients with breast cancer in comparison with those without breast cancer. Circulating A-FABP released by adipose tissue directly targeted mammary tumor cells, enhancing tumor stemness and aggressiveness through activation of the IL-6/STAT3/ALDH1 pathway. Importantly, genetic deletion of A-FABP successfully reduced tumor ALHD1 activation and obesity-associated mammary tumor growth and development in different mouse models. Collectively, these data suggest circulating A-FABP as a new link between obesity and breast cancer risk, thereby revealing A-FABP as a potential new therapeutic target for treatment of obesity-associated cancers.
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•Circulating levels of A-FABP are elevated in obesity-associated breast cancer•Soluble A-FABP promotes mammary tumor stemness and aggressiveness•A-FABP-induced ALDH1 activity is dependent on IL-6/STAT3 signaling•A-FABP deficiency uncouples HFD-induced obesity and mammary tumor development
The links between obesity and cancer are not well understood. Hao et al. show that circulating adipose fatty acid binding protein (A-FABP) increases in obesity and promotes breast cancer by increasing mammary tumor stemness and aggressiveness through an IL-6/STAT3/ALDH1 axis. A-FABP could be a potential therapeutic target for obesity-associated cancers.
The gut microbiota can be altered by dietary interventions to prevent and treat various diseases. However, the mechanisms by which food products modulate commensals remain largely unknown. We ...demonstrate that plant-derived exosome-like nanoparticles (ELNs) are taken up by the gut microbiota and contain RNAs that alter microbiome composition and host physiology. Ginger ELNs (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent manner and contain microRNAs that target various genes in Lactobacillus rhamnosus (LGG). Among these, GELN mdo-miR7267-3p-mediated targeting of the LGG monooxygenase ycnE yields increased indole-3-carboxaldehyde (I3A). GELN-RNAs or I3A, a ligand for aryl hydrocarbon receptor, are sufficient to induce production of IL-22, which is linked to barrier function improvement. These functions of GELN-RNAs can ameliorate mouse colitis via IL-22-dependent mechanisms. These findings reveal how plant products and their effects on the microbiome may be used to target specific host processes to alleviate disease.
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•Plant exosome-like nanoparticles (ELNs) are taken up by gut bacteria•The lipid composition of ELNs determines uptake by specific bacteria•ELN RNAs affect bacterial genes, notably affecting Lactobacillus production of I3A•ELN-mediated I3A alterations affect IL-22 production, resulting in ameliorated colitis
Teng et al. show that exosome-like nanoparticles (ELNs) from edible plants such as ginger are preferentially taken up by gut bacteria in an ELN lipid-dependent manner. ELN RNAs regulate gut microbiota composition and localization as well as host physiology, notably enhancing gut barrier function to alleviate colitis.
Therapeutic macromolecules such as proteins are conventionally administered via bolus injection, an approach that presents significant limitations. Sustained-release biodegradable nano/microsphere ...depots, on the other hand, represent a more physiological delivery tool for biologics. Here, we focus on an emerging novel application of this technology, i.e., cytokine-encapsulated biodegradable microspheres as immune therapeutics. The overall pre-clinical experience, recent advances and the clinical potential of such formulations are discussed.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Intratracheal administration of a novel IL-10 formulation suppressed IL-17-driven, CD4
T cell-dependent tumorigenesis in the LSL-K-ras
murine lung cancer model. Analysis of lung lymphocyte ...populations demonstrated that antitumor activity of IL-10 was associated with a 5-fold decline in Th17 cell prevalence and a concurrent suppression of inflammatory M1-like macrophage activity. Further phenotypic characterization revealed that macrophages and dendritic cells, but not Th17 cells, expressed IL-10RA on the cell surface with the CD11b
F4/80
CX3CR1
interstitial macrophages representing the dominant IL-10RA
subset. Consistent with these observations, in vitro stimulation of sorted CD4
T cells with IL-10 did not affect their ability to produce IL-17, whereas similar treatment of purified interstitial macrophages resulted in a dramatic M1 to M2 phenotypic switch. Importantly, preconditioning of macrophages (but not of CD4
T cells) with IL-10 led to potent suppression of CD4
T cell IL-17 production in an in vitro coculture assay, suggesting that IL-10 suppressed Th17 cell activity primarily via its upstream effects on macrophages. In support of this notion, in vivo macrophage depletion resulted in a 5-fold decline in Th17 cell numbers and a concurrent 6-fold reduction in tumor burden. Collectively, these data demonstrate that in the LSL-K-ras
murine lung cancer model, inflammatory macrophage-Th17 cell axis is critical to tumorigenesis and that IL-10 blocks this process primarily via a direct effect on the former. Inhaled IL-10 formulations may be of use in prophylaxis against lung cancer in high-risk patients.
Tumor-associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically relevant markers for ...protumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid-binding protein (A-FABP) in TAM promotes breast cancer progression. Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11b
F4/80
MHCII
Ly6C
phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NFκB/
pathway. Collectively, our results suggest A-FABP as a new functional marker for protumor TAM.
These findings identify A-FABP as a functional marker for protumor macrophages, thus offering a new target for tumor immunotherapy.
.
Tumors that develop in the genetic LSL-K-ras
G12D
murine lung cancer model are resistant to anti-PD-1 antibody treatment. Analysis of tumor-bearing lungs from anti-PD-1-treated mice revealed an up to ...2.5-fold increase in IL-17-producing T-cells, with minimal change in CD8
+
T-cell activity. Neutralization of IL-17 concurrent with anti-PD-1 treatment on the other hand, resulted in robust CD8
+
T-cell activation and a threefold reduction in tumor burden. Loss-of-function studies demonstrated that anti-PD-1 driven activation of CD4
+
and γδTCR
+
T-cells contributed to IL-17-mediated de-sensitization of CD8
+
cytotoxic T-cells (CTL) to therapy; and that CTL activation was critical to tumor eradication. Importantly, post-therapy lung Th17 cell prevalence and activity prognosticated treatment efficacy. Consistent with the murine data, analysis of tumor biopsy samples from non-small cell lung cancer (NSCLC) patients revealed that pre-therapy intratumoral CD8
+
/RORc
+
cell ratio correlated with response to immune checkpoint blockade (ICB). These findings provide the initial evidence for a new mechanism of ICB resistance in lung cancer.
Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in ...different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in protumor macrophages. Compared with fatty acid (FA) components in both HFDs, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the protumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA-mediated ROS production and macrophage death
and
. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated protumor macrophage death in an A-FABP-dependent manner. SIGNIFICANCE: This study provides mechanistic insight into dietary supplementation with fish oil for breast cancer prevention and advances a new concept that not all HFDs leading to obesity are tumorigenic. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/12/2564/F1.large.jpg.
Bark protects the tree against environmental insults. Here, we analyzed whether this defensive strategy could be utilized to broadly enhance protection against colitis. As a proof of concept, we show ...that exosome‐like nanoparticles (MBELNs) derived from edible mulberry bark confer protection against colitis in a mouse model by promoting heat shock protein family A (Hsp70) member 8 (HSPA8)‐mediated activation of the AhR signaling pathway. Activation of this pathway in intestinal epithelial cells leads to the induction of COP9 Constitutive Photomorphogenic Homolog Subunit 8 (COPS8). Utilizing a gut epithelium‐specific knockout of COPS8, we demonstrate that COPS8 acts downstream of the AhR pathway and is required for the protective effect of MBELNs by inducing an array of anti‐microbial peptides. Our results indicate that MBELNs represent an undescribed mode of inter‐kingdom communication in the mammalian intestine through an AhR‐COPS8‐mediated anti‐inflammatory pathway. These data suggest that inflammatory pathways in a microbiota‐enriched intestinal environment are regulated by COPS8 and that edible plant‐derived ELNs may hold the potential as new agents for the prevention and treatment of gut‐related inflammatory disease.
Synopsis
Mulberry bark derived exosome‐like nanoparticles (MBELNs) prevent gut inflammation via plant heat shock protein HSPA8‐mediated activation of AhR/COPS8 pathways. Treatment with MBELNs promotes the restoration of gut microbiome homeostasis, ameliorating intestinal inflammatory pathologies.
Mulberry bark derived exosome‐like nanoparticles (MBELNs) prevent mouse colitis via the AhR/COPS8 pathway.
Binding of MBELN‐derived heat shock protein HSPA8 to AhR leads to the activation of AhR signaling.
Activation of AhR leads to the induction of an array of anti‐microbial peptides (AMPs) via COP9/COPS8.
AhR/COPS8‐dependent induction of AMPs inhibits intestinal inflammation and alters fecal gut microbiota composition.
Mulberry bark derived exosome‐like nanoparticles (MBELNs) prevent gut inflammation via plant heat shock protein HSPA8‐mediated activation of AhR/COPS8 pathways. Treatment with MBELNs promotes the restoration of gut microbiome homeostasis, ameliorating intestinal inflammatory pathologies.
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