CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells

Chang, Alan L.; Miska, Jason; Wainwright, Derek A.; Dey, Mahua; Rivetta, Claudia V.; Yu, Dou; Kanojia, Deepak; Pituch, Katarzyna C.; Qiao, Jian; Pytel, Peter; Han, Yu; Wu, Meijing; Zhang, Lingjiao; Horbinski, Craig; Ahmed, Atique U.; Lesniak, Maciej S.

doi:10.1158/0008-5472.can-16-0144

Cited by 465 publications

(457 citation statements)

References 43 publications

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“…MCP-1 is often reported as a key tumor-derived factor responsible for myeloid cell accumulation. 40,44,45 These studies have led to the proposal of MCP-1 blockade as a treatment for GBM. 46,47 A detailed examination of human gliomas demonstrated that MCP-3, not MCP-1 correlates with myeloid cell accumulation in glioblastoma, 48 calling into question the utility of MCP-1 inhibition in preventing TAM infiltration.…”

Section: Resultsmentioning

confidence: 99%

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

et al. 2018

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Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue.Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

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Section: Resultsmentioning

confidence: 99%

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

et al. 2018

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“…Previous report indicated that CCL2 is required for recruitment of macrophage and accumulation of MDSCs in the tumor microenvironment (16,18), suggesting that high expression of HOTAIR in cancer cells recruit TAMs/MDSCs through the secretion of CCL2, resulting in promoting tumor growth and metastasis. To the best of our knowledge, this is the first report that HOTAIR can affect the surrounding immune cells through humoral factor such as CCL2.…”

Section: Discussionmentioning

confidence: 99%

“…The CCL2 is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including HCC (16). Furthermore, recent study suggested that microenvironment-derived CCL2 results in the accumulation of MDSCs in glioma (18). Thus, CCL2 is critical for immunosuppression to promote cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA HOTAIR up‑regulates chemokine (C‑C motif) ligand 2 and promotes proliferation of macrophages and myeloid‑derived suppressor cells in hepatocellular carcinoma cell lines

et al. 2017

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Abstract. Accumulating evidence demonstrated that Hox antisense intergenic RNA (HOTAIR) serves essential roles in the development and metastasis of several types of cancer. In hepatocellular carcinoma (HCC), high expression of HOTAIR is associated with poor prognosis, and HOTAIR regulates cell migration and proliferation. However, the downstream molecular targets of HOTAIR depend on the cancer cell types, and little is known about the precise molecular mechanisms of HOTAIR involved in cancer development. The present study investigated the role of HOTAIR in HCC cell lines. Notably, the overexpression of HOTAIR in HCC cell lines did not affect cell migration and proliferation capability. In the microarray analysis, C-C motif chemokine ligand (CCL)2 was identified to be differentially expressed in HOTAIR-overexpressing cells, and it was confirmed that HOTAIR promotes the secretion of CCL2. Furthermore, it was revealed that the proportion of macrophages and myeloid-derived suppressor cells (MDSCs) were increased when peripheral blood mononuclear cells were co-cultured with HOTAIR-overexpressing cells. Collectively, these data suggest that HOTAIR regulates CCL2 expression, which may be involved in the recruitment of macrophages and MDSCs to the tumor microenvironment. IntroductionHox antisense intergenic RNA (HOTAIR), a lncRNA that acts as an oncogenic molecule in various types of cancer, is localized to the HOXC gene cluster. HOTAIR interacts with PRC2 (polycomb repressive complex 2) to enhance H3K27 trimethylation, and thereby decreases the expression of a large number of genes. Several groups, including our laboratory, have reported that high HOTAIR expression is correlated with a poor prognosis in several types of cancer, including breast (1), colorectal (2), non-small lung cell (3), and gastric cancer (4). Interestingly, recent report suggested that effects of HOTAIR are strongly tissue-dependent and can even differ within the same type of cancer (5). Thus, the underlying mechanism by which HOTAIR is involved in malignant progression remains uncertain.Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer and second leading cause of cancer-related mortality worldwide. More than 600,000 deaths are associated with HCC every year worldwide (6). Previous report suggested that the expression of HOTAIR is associated with tumor recurrence and poor prognosis in hepatocellular carcinoma (7,8). Several in vitro analyses were reported using HCC cell line, HepG2; HOTAIR is a FOXC1-activated driver of malignancy, which acts in part through the repression of miR-1 in HepG2 cells (9). HOTAIR silence activates P16 Ink4a and P14 ARF signaling by enhancing miR-218 expression and suppressing Bmi-1 expression, resulting in the suppression of tumorigenesis in HepG2 cells (10). Introduction of human HOTAIR into HepG2 cells revealed that HOTAIR promoted more rapid proliferation (7). Although different intracellular signaling are expected among multiple HCC cell lines, the research of HOTAIR using HCC cell lines except for...

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“…More than 32 have been approved for systemic malignancies [12,33]. Unfortunately, not one has shown consistent efficacy against CNS tumors despite several achieving relatively high brain concentration.…”

Section: Clinical Reality and Pharmaceutical Challengesmentioning

confidence: 99%

“…Furthermore, it was shown that astrocytederived exosomal miR-19a reversibly downregulated Phosphate and tensin homolog expression in breast-brain metastases, leading to increased secretion of CCL2, recruitment of myeloid cells and promotion of metastases. Ablation of CCL2 inhibited brain metastasis in vivo, suggesting the potential for using CCL2 inhibitors as a therapeutic approach [33].…”

Section: Drug Targets and Cns Tumor Microenvironmentmentioning

confidence: 99%

CNS Anticancer Drug Discovery and Development: 2016 conference insights

Levin

Abrey

Heffron³

et al. 2017

CNS Oncol.

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The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669-286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/ biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time-and cost-efficient clinical trials based on surrogate end points.

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CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells

Cited by 465 publications

References 43 publications

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

Long non-coding RNA HOTAIR up‑regulates chemokine (C‑C motif) ligand 2 and promotes proliferation of macrophages and myeloid‑derived suppressor cells in hepatocellular carcinoma cell lines

CNS Anticancer Drug Discovery and Development: 2016 conference insights

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