Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.

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Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00467.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. H2042-H2057 ◽

Cited By ~ 25

Author(s):

Sanjukta Chakraborty ◽

Scott D. Zawieja ◽

Wei Wang ◽

Yang Lee ◽

Yuan J. Wang ◽

...

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Contractile Activity ◽

Macrophage Polarization ◽

Lymphatic Vessels ◽

Innate Immune ◽

Innate Immune Cells ◽

Lymphatic Function ◽

Inflammatory Conditions ◽

Rat Mesentery

Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction.

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Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820276116 ◽

2019 ◽

Vol 116 (30) ◽

pp. 14947-14954 ◽

Cited By ~ 11

Author(s):

Jonghyuck Park ◽

Yining Zhang ◽

Eiji Saito ◽

Steve J. Gurczynski ◽

Bethany B. Moore ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Immune Cells ◽

Macrophage Polarization ◽

Innate Immune ◽

Control Group ◽

Innate Immune Cells ◽

Benefit Ratio ◽

Cord Injury

Traumatic primary spinal cord injury (SCI) results in paralysis below the level of injury and is associated with infiltration of hematogenous innate immune cells into the injured cord. Methylprednisolone has been applied to reduce inflammation following SCI, yet was discontinued due to an unfavorable risk-benefit ratio associated with off-target effects. In this study, i.v. administered poly(lactide-coglycolide) nanoparticles were internalized by circulating monocytes and neutrophils, reprogramming these cells based on their physicochemical properties and not by an active pharmaceutical ingredient, to exhibit altered biodistribution, gene expression, and function. Approximately 80% of nanoparticle-positive immune cells were observed within the injury, and, additionally, the overall accumulation of innate immune cells at the injury was reduced 4-fold, coinciding with down-regulated expression of proinflammatory factors and increased expression of antiinflammatory and proregenerative genes. Furthermore, nanoparticle administration induced macrophage polarization toward proregenerative phenotypes at the injury and markedly reduced both fibrotic and gliotic scarring 3-fold. Moreover, nanoparticle administration with the implanted multichannel bridge led to increased numbers of regenerating axons, increased myelination with about 40% of axons myelinated, and an enhanced locomotor function (score of 6 versus 3 for control group). These data demonstrate that nanoparticles provide a platform that limits acute inflammation and tissue destruction, at a favorable risk-benefit ratio, leading to a proregenerative microenvironment that supports regeneration and functional recovery. These particles may have applications to trauma and potentially other inflammatory diseases.

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Nanoparticles Targeting Innate Immune Cells in Tumor Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms221810009 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10009

Author(s):

Hochung Jang ◽

Eun Hye Kim ◽

Sung-Gil Chi ◽

Sun Hwa Kim ◽

Yoosoo Yang

Keyword(s):

Dendritic Cells ◽

Tumor Microenvironment ◽

Immune Cells ◽

Immune Checkpoint ◽

Suppressor Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Myeloid Derived Suppressor Cells ◽

Tumor Microenvironments ◽

Clinical Benefits

A variety of innate immune cells such as macrophages, dendritic cells, myeloid-derived suppressor cells, natural killer cells, and neutrophils in the tumor microenvironments, contribute to tumor progression. However, while several recent reports have studied the use of immune checkpoint-based cancer immunotherapy, little work has focused on modulating the innate immune cells. This review focuses on the recent studies and challenges of using nanoparticles to target innate immune cells. In particular, we also examine the immunosuppressive properties of certain innate immune cells that limit clinical benefits. Understanding the cross-talk between tumors and innate immune cells could contribute to the development of strategies for manipulating the nanoparticles targeting tumor microenvironments.

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