MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.

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Exosomal miR-222 from adriamycin-resistant MCF-7 breast cancer cells promote macrophages M2 polarization via PTEN/Akt to induce tumor progression

Aging ◽

10.18632/aging.202802 ◽

2021 ◽

Author(s):

Wei-Xian Chen ◽

Dan-Dan Wang ◽

Bei Zhu ◽

Yi-Zhi Zhu ◽

Lin Zheng ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

M2 Polarization ◽

Mcf 7

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Dynamic Changes in Macrophage Polarization Correlate with Progression and Response in CNS Lymphoma: Insights Into the Transcriptome of Lymphoma-Associated M2 Macrophages,

Blood ◽

10.1182/blood.v118.21.3219.3219 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3219-3219

Author(s):

Cigall Kadoch ◽

Valerie Wong ◽

Lingjing Chen ◽

Anna Bet-Lachin ◽

Ritu Roy ◽

...

Keyword(s):

Tumor Progression ◽

Transcriptional Profiling ◽

Macrophage Polarization ◽

Cns Lymphoma ◽

M2 Macrophages ◽

Activated Macrophages ◽

M2 Polarization ◽

Macrophage Subpopulations ◽

Cns Lymphomas ◽

Profiling Analysis

Abstract Abstract 3219 Background: Macrophages are an important component of the tumor microenvironment and the immune response to malignancy. Classically activated (M1-polarized) macrophages exhibit anti-tumor effect, while alternatively activated (M2-polarized) macrophages promote tissue repair, angiogenesis, immunosuppression and tumor progression. To date, the vast majority of studies on macrophage phenotype and polarization have been based upon in vitro studies or murine model systems. We tested the hypothesis that distinct macrophage subsets can be identified within the microenvironment of lymphoid tumors and that the relative proportion of M1:M2 macrophages correlates with therapeutic response and/or resistance. In addition, we postulated that transcriptional analysis of distinct macrophage subpopulations would provide insights into mechanisms by which M2 macrophages promote tumor progression and reveal novel mechanisms which direct the interconversion of activated macrophages between classical and alternative activation states. Our focus has been on the evaluation of the tumor microenvironment in CNS lymphomas, the cerebrospinal fluid (CSF), which is enriched in inflammatory cells including activated CD14+ macrophages that we hypothesized would exhibit phenotypic features consistent with M1 and M2 polarization. Methods: We developed a novel 9-parameter flow-cytometric method to isolate distinct subpopulations of activated macrophages from CSF and peripheral blood. The method identifies macrophages with M1 features based upon expression of nitric oxide synthase (iNOS) and M2 macrophages on the basis of low-expression of iNOS and high expression of scavenger receptors CD206, CD209 and CD36. Subpopulations of macrophages were quantified and analyzed by FACS and transcriptional profiling (Affymetrix Gene Chip 1.0 ST). Serial analysis of CSF was performed in CNS lymphoma patients to correlate macrophage polarization states with response and/or progression. Parallel analyses were performed in blood in patients with non-Hodgkin lymphoma (NHL) to control conditions including infections and/or sarcoid. Results: At least four distinct subpopulations of activated macrophages were identified in CSF in association with CNS lymphoma (N=30) and controls (N=28). A greater than six-fold increase in the proportion of M2 macrophages was detected in CSF of CNS lymphoma patients compared to control subjects (p<0.001). By contrast, the proportion of CSF macrophages with M1 features was similar between NHL and controls. Moreover, peripheral blood macrophages from CNS lymphoma patients did not demonstrate significant M2-polarization. Serial analysis demonstrated that M2 polarization of CSF macrophages correlated with tumor progression and/or response. Transcriptional profiling analysis was conducted on macrophage subpopulations isolated from CSF of CNS lymphoma patients and controls. While few significant transcriptional differences were identified between M1 and unpolarized (Mnaive) macrophages, the transcriptional comparison of M2 vs. M1 as well as M2 vs. Mnaive macrophage subpopulations revealed several hundred differentially expressed genes with significant adjusted p-values. Pathway Analysis (Ingenuity) suggested mechanisms strongly associated with the M2 phenotype including activation of Notch signaling. Transcripts associated with short survival were most strongly expressed by M2 macrophages and included Ephrin A4 and lymphoid chemokines such as CXCL-13. The prognostic significance of high CXCL-13 and Ephrin A4 expression were confirmed by ELISA in an independent validation set of cases. Conclusions: We believe this to be the first application of flow-cytometry to define the phenotypes and dynamic interconversion of intratumoral macrophages within the lymphoma microenvironment and the first correlation of M2 macrophages with the evolution of resistance to therapy. In addition, this dataset provides the first in-depth transcriptional profiling analysis of in vivo human macrophage subpopulations and suggests novel mechanisms by which tumor-associated macrophages may facilitate lymphoma progression via the regulation of the metabolic microenvironment, angiogenesis, tumor invasion and immunosuppression. Based upon our additional preliminary data, we hypothesize that these results may be relevant to a variety of lymphoid tumors. Disclosures: Off Label Use: We will discuss the use of rituximab within the leptomeningeal compartment to treat recurrent/refractory CNS lymphomas.

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CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model

Immunology ◽

10.1111/imm.12293 ◽

2014 ◽

Vol 143 (1) ◽

pp. 109-119 ◽

Cited By ~ 42

Author(s):

Steve Oghumu ◽

Sanjay Varikuti ◽

Cesar Terrazas ◽

Dmitri Kotov ◽

Mohd W. Nasser ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Cancer Model ◽

M2 Polarization ◽

Breast Cancer Model

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Ethanol Extract of Mylabris phalerata Inhibits M2 Polarization Induced by Recombinant IL-4 and IL-13 in Murine Macrophages

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/4218468 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Hwan-Suck Chung ◽

Bong-Seon Lee ◽

Jin Yeul Ma

Keyword(s):

Tumor Progression ◽

Ethanol Extract ◽

Mechanism Study ◽

M1 Macrophages ◽

Transwell Migration Assay ◽

Migration Assay ◽

Arginase 1 ◽

Anticancer Effects ◽

M2 Polarization ◽

Stat3 Phosphorylation

Mylabris phalerata (MP) is an insect used in oriental herbal treatments for tumor, tinea infections, and stroke. Recent studies have shown that tumor-associated macrophages (TAM) have detrimental roles such as tumor progression, angiogenesis, and metastasis. Although TAM has phenotypes and characteristics in common with M2-polarized macrophages, M1 macrophages have tumor suppression and immune stimulation effects. Medicines polarizing macrophages to M1 have been suggested to have anticancer effects via the modulation of the tumor microenvironment. In this line, we screened oriental medicines to find M1 polarizing medicines in M2-polarized macrophages. Among approximately 400 types of oriental medicine, the ethanol extract of M. phalerata (EMP) was the most proficient in increasing TNF-α secretion in M2-polarized macrophages and TAM. Although EMP enhanced the levels of an M1 cytokine (TNF-α) and a marker (CD86), it significantly reduced the levels of an M2 marker (arginase-1) in M2-polarized macrophages. In addition, EMP-treated macrophages increased the levels of M1 markers (Inos and Tnf-α) and reduced those of the enhanced M2 markers (Fizz-1, Ym-1, and arginase-1). EMP-treated macrophages significantly reduced Lewis lung carcinoma cell migration in a transwell migration assay and inhibited EL4-luc2 lymphoma proliferation. In our mechanism study, EMP was found to inhibit STAT3 phosphorylation in M2-polarized macrophages. These results suggest that EMP is effective in treating TAM-mediated tumor progression and metastasis.

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Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist

PLoS ONE ◽

10.1371/journal.pone.0248996 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248996

Author(s):

Gao Sheng ◽

Hongyan Yuan ◽

Lu Jin ◽

Suman Ranjit ◽

Julia Panov ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Tumor Progression ◽

Immune Tolerance ◽

Cancer Survival ◽

Immune Surveillance ◽

Tumor Development ◽

Suppressor Cells ◽

Inflammatory Factors ◽

Immune Tolerant

One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent immune surveillance. One such element associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poor survival. Fibrosis is caused by inflammatory factors and remodeling of the extracellular matrix that elicit an immune tolerant microenvironment. To address the role of fibrosis in tumorigenesis, we developed NeuT/ATTAC transgenic mice expressing a constitutively active NeuT/erbB2 transgene, and an inducible, fat-directed caspase-8 fusion protein, which upon activation results in selective and partial ablation of mammary fat and its replacement with fibrotic tissue. Induction of fibrosis in NeuT/ATTAC mice led to more rapid tumor development and an inflammatory and fibrotic stromal environment. In an effort to explore therapeutic options that could reduce fibrosis and immune tolerance, mice were treated with the oxysterol liver X receptor (LXR) pan agonist, N,N-dimethyl-3-β-hydroxy-cholenamide (DMHCA), an agent known to reduce fibrosis in non-malignant diseases. DMHCA reduced tumor progression, tumor multiplicity and fibrosis, and improved immune surveillance by reducing infiltrating myeloid-derived suppressor cells and increasing CD4 and CD8 effector T cells. These effects were associated with downregulation of an LXR-dependent gene network related to reduced breast cancer survival that included Spp1, S100a9, Anxa1, Mfge8 and Cd14. These findings suggest that the use of DMHCA may be a potentially effective approach to reduce desmoplasia and immune tolerance and increase the efficacy of cancer therapy.

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LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization

Cell Death and Disease ◽

10.1038/s41419-019-2077-0 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 25

Author(s):

Zhen-xing Liang ◽

Hua-shan Liu ◽

Feng-wei Wang ◽

Li Xiong ◽

Chi Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Tumor Resection ◽

Poor Prognostic Factor ◽

Mesenchymal Transition ◽

M2 Polarization

Abstract Metastasis is a well-known poor prognostic factor in cancer. However, the mechanisms how long non-coding RNAs (lncRNAs) regulate metastasis in colorectal cancer (CRC) remain largely unknown. Besides, tumor-associated macrophages (TAMs) play an important role in tumor progression, yet the contribution of lncRNA-mediated crosstalk between TAMs and CRC cells to tumor progression is not well understood. In this study, we report that lncRNA RPPH1 was significantly upregulated in CRC tissues, and the RPPH1 overexpression was associated with advanced TNM stages and poor prognosis. RPPH1 was found to promote CRC metastasis in vitro and in vivo. Mechanistically, RPPH1 induced epithelial–mesenchymal transition (EMT) of CRC cells via interacting with β-III tubulin (TUBB3) to prevent its ubiquitination. Furthermore, CRC cell-derived exosomes transported RPPH1 into macrophages which mediate macrophage M2 polarization, thereby in turn promoting metastasis and proliferation of CRC cells. In addition, exosomal RPPH1 levels in blood plasma turned out to be higher in treatment-naive CRC patients but lower after tumor resection. Compared to CEA and CA199, exosomal RPPH1 in CRC plasma displayed a better diagnostic value (AUC = 0.86). Collectively, RPPH1 serves as a potential therapeutic and diagnostic target in CRC.

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