Dataset Information

Anti-tumor macrophages activated by ferumoxytol combined or surface-functionalized with the TLR3 agonist poly (I : C) promote melanoma regression.

ABSTRACT: Macrophages orchestrate inflammation and control the promotion or inhibition of tumors and metastasis. Ferumoxytol (FMT), a clinically approved iron oxide nanoparticle, possesses anti-tumor therapeutic potential by inducing pro-inflammatory macrophage polarization. Toll-like receptor 3 (TLR3) activation also potently enhances the anti-tumor response of immune cells. Herein, the anti-tumor potential of macrophages harnessed by FMT combined with the TLR3 agonist, poly (I:C) (PIC), and FP-NPs (nanoparticles composed of amino-modified FMT (FMT-NH₂) surface functionalized with PIC) was explored. Methods: Proliferation of B16F10 cells co-cultured with macrophages was measured using immunofluorescence or flow cytometry (FCM). Phagocytosis was analyzed using FCM and fluorescence imaging. FP-NPs were prepared through electrostatic interactions and their properties were characterized using dynamic light scattering, transmission electron microscopy, and gel retardation assay. Anti-tumor and anti-metastasis effects were evaluated in B16F10 tumor-bearing mice, and tumor-infiltrating immunocytes were detected by immunofluorescence staining and FCM. Results: FMT, PIC, or the combination of both hardly impaired B16F10 cell viability. However, FMT combined with PIC synergistically inhibited their proliferation by shifting macrophages to a tumoricidal phenotype with upregulated TNF-? and iNOS, increased NO secretion and augmented phagocytosis induced by NOX2-derived ROS in vitro. Combined treatment with FMT/PIC and FMT-NH₂/PIC respectively resulted in primary melanoma regression and alleviated pulmonary metastasis with elevated pro-inflammatory macrophage infiltration and upregulation of pro-inflammatory genes in vivo. In comparison, FP-NPs with properties of internalization by macrophages and accumulation in the lung produced a more pronounced anti-metastatic effect accompanied with decreased myeloid-derived suppressor cells, and tumor-associated macrophages shifted to M1 phenotype. In vitro mechanistic studies revealed that FP-NPs nanoparticles barely affected B16F10 cell viability, but specifically retarded their growth by steering macrophages to M1 phenotype through NF-?B signaling. Conclusion: FMT synergized with the TLR3 agonist PIC either in combination or as a nano-composition to induce macrophage activation for primary and metastatic melanoma regression, and the nano-composition of FP-NPs exhibited a more superior anti-metastatic efficacy.

SUBMITTER: Zhao J

PROVIDER: S-EPMC6299704 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Anti-tumor macrophages activated by ferumoxytol combined or surface-functionalized with the TLR3 agonist poly (I : C) promote melanoma regression.

Zhao Jiaojiao J Zhang Zhengkui Z Xue Yaxian Y Wang Guoqun G Cheng Yuan Y Pan Yuchen Y Zhao Shuli S Hou Yayi Y

Theranostics 20181129 22

Macrophages orchestrate inflammation and control the promotion or inhibition of tumors and metastasis. Ferumoxytol (FMT), a clinically approved iron oxide nanoparticle, possesses anti-tumor therapeutic potential by inducing pro-inflammatory macrophage polarization. Toll-like receptor 3 (TLR3) activation also potently enhances the anti-tumor response of immune cells. Herein, the anti-tumor potential of macrophages harnessed by FMT combined with the TLR3 agonist, poly (I:C) (PIC), and FP-NPs (nano ...[more]

PMID: 30613299

Similar Datasets

Project description:Background: Regulating the polarization of macrophages to antitumor M1 macrophages is a promising strategy for overcoming the immunosuppression of the tumor microenvironment for cancer therapy. Ferumoxytol (FMT) can not only serve as a drug deliver agent but also exerts anti-tumor activity. β-glucan has immuno-modulating properties to prevent tumor growth. Thus, a nanocomposite of FMT surface-coated with β-glucan (FMT-β-glucan) was prepared to explore its effect on tumor suppression. Methods: Male B16F10 melanoma mouse model was established to explore the antitumor effect of FMT-β-glucan. The viability and apoptotic rates of B16F10 cells were detected by cell counting kit-8 and Annexin-V/PI experiments. The levels of M1 markers were quantified by quantitative reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay. Phagocytic activity and intracellular reactive oxygen species (ROS) in macrophages were evaluated by the neutral red uptake assay and flow cytometry, respectively. Small interfering RNA (siRNA) transfection was applied to knock down the Dectin-1 gene in RAW 264.7 cells. Results: FMT-β-glucan suppressed tumor growth to a greater extent and induced higher infiltration of M1 macrophages than the combination of FMT and β-glucan (FMT+β-glucan) in vivo. In vitro, supernatant from FMT-β-glucan-treated RAW 264.7 cells led to lower cell viability and induced more apoptosis of B16F10 cells than that from the FMT+β-glucan group. Moreover, FMT-β-glucan boosted the expression of M1 type markers, and increased phagocytic activity and ROS in RAW 264.7 cells. Further research indicated that FMT-β-glucan treatment promoted the level of Dectin-1 on the surface of RAW 264.7 cells and that knockdown of Dectin-1 abrogated the phosphorylation levels of several components in MAPK and NF-κB signaling. Conclusion: The nanocomposite FMT-β-glucan suppressed melanoma growth by inducing the M1 macrophage-activated tumor microenvironment.

Project description:Background & aimFollowing acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI).MethodsSeveral phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice.ResultsBMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings.ConclusionWe identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury.Lay summaryAfter an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury.

Dataset Information

Anti-tumor macrophages activated by ferumoxytol combined or surface-functionalized with the TLR3 agonist poly (I : C) promote melanoma regression.

Publications

Anti-tumor macrophages activated by ferumoxytol combined or surface-functionalized with the TLR3 agonist poly (I : C) promote melanoma regression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets