Myeloid-derived suppressor cell accumulation in renal cell carcinoma is correlated with CCL2, IL-17 and IL-18 expression in blood and tumors

Guan, Xiaodong; Liu, Zhiyu; Zhang, Jianhua; Jin, Xunbo

doi:10.17219/acem/70065

Cited by 35 publications

(31 citation statements)

References 22 publications

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“…C-C motif chemokine ligand 2 (CCL2) was initially characterized as a cytokine, which, upon interaction with its correspondent receptor, CCR2, on circulating monocytes, could expedite chemotaxis to areas of inflammation [21,32]. It has been shown that in in vitro experiments of human cancer models, secretion of tumor-derived CCL2 attracts CCR2 expressing MDSCs towards the cytokine [21], with evidence provided by Guan et al positively correlating the amount of CCL2 to MDSC accumulation and immunosuppressive capacity [33]. In a similar way, the chemokine interleukin-8 (IL-8, CXCL8) is a chemo attractant that was found to be released by cancer cells and to ulcerate cells of myeloid lineages upon binding to G protein-coupled receptors C-X-C motif chemokine receptor 1 and 2 (CXCR1 and CXCR2) [32,34], while the CCL3/CCR5 axis was shown to aid in the maintenance of immunosuppressive myeloid cells to the tumor niches [21].…”

Section: Accumulation Of Mdscs To Tumor Sitesmentioning

confidence: 99%

“…In a similar way, the chemokine interleukin-8 (IL-8, CXCL8) is a chemo attractant that was found to be released by cancer cells and to ulcerate cells of myeloid lineages upon binding to G protein-coupled receptors C-X-C motif chemokine receptor 1 and 2 (CXCR1 and CXCR2) [32,34], while the CCL3/CCR5 axis was shown to aid in the maintenance of immunosuppressive myeloid cells to the tumor niches [21]. Guan et al also highlighted that IL-17, a pro-inflammatory cytokine mainly secreted by Th17 cells, is over expressed by malignant cells and promotes the translocation of MDSCs from the periphery to the tumor site [33].…”

Section: Accumulation Of Mdscs To Tumor Sitesmentioning

confidence: 99%

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Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

Vetsika

Koukos

Κotsakis

2019

Cells

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Myeloid-derived suppressor cells (MDSCs) constitute a vast population of immature myeloid cells implicated in various conditions. Most notably, their role in cancer is of great complexity. They exert immunosuppressive functions like hampering cancer immunity mediated by T lymphocytes and natural killer cells, while simultaneously they can recruit T regulatory cells to further promote immunosuppression, thus shielding tumor cells against the immune defenses. In addition, they were shown to support tumor invasion and metastasis by inducing vascularization. Yet again, in order to exert their angiogenic activities, they do have at their disposal a variety of occasionally overlapping mechanisms, mainly driven by VEGF/JAK/STAT signaling. In this concept, they have risen to be a rather attractive target for therapies, including depletion or maturation, so as to overcome cancer immunity and suppress angiogenic activity. Even though, many studies have been conducted to better understand these cells, there is much to be done yet. This article hopes to shed some light on the paradoxal complexity of these cells, while elucidating some of the key features of MDSCs in relation to immunosuppression and, most importantly, to the vascularization processes, along with current therapeutic options in cancer, in relation to MDSC depletion.

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Section: Accumulation Of Mdscs To Tumor Sitesmentioning

confidence: 99%

Section: Accumulation Of Mdscs To Tumor Sitesmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

Vetsika

Koukos

Κotsakis

2019

Cells

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“…All of these acquired features can be partially blocked by inhibitors of GM-CSF or STAT3, suggesting that the production of GM-CSF by the tumor cells is one of the means by which MDSC are induced and recruited by RCC. In a study focused specifically on RCC, the influx of MDSC was found to be correlated with levels of CCL2 (MCP-1), IL-17, and IL-18, all of which were abundantly expressed in tumor tissue and present in the blood of patients [19]. Najjar et al observed a correlation between the infiltration of the neutrophilic type of MDSC in RCC with the expression of IL-1β, IL-8, CXCL5, and Mip-1α [20].…”

Section: Myeloid-derived Suppressor Cells (Mdsc)mentioning

confidence: 99%

The tumor microenvironment in renal cell cancer

Mier

2019

Current Opinion in Oncology

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Purpose of review: In addition to the provision of nutrients and growth factors that facilitate tumor cell proliferation and metastasis, the tumor microenvironment (MEV) restricts immune surveillance of tumor-associated antigens and limits the efficacy of immune checkpoint inhibitors (ICIs), tumor vaccines, and other immune therapies. This review will focus on the immunosuppressive mechanisms operative within the tumor MVE of renal cell carcinoma (RCC). Recent findings: Several of the immunosuppressive mechanisms within the tumor MEV have been identified and are potentially druggable. Clinical trials with agents that target several of these inhibitory pathways are currently underway. Summary: Although RCC is one of several tumor types responsive to ICIs, the effectiveness of these agents is likely to be limited by the various tumor-infiltrating bone marrow-derived myeloid cells that comprise the MEV. Several strategies to combat the recruitment of these cells into tumor tissue or to neutralize their immunosuppressive function have shown encouraging results in animal tumor models and clinical trials. Keywords microenvironment (MEV); renal cell carcinoma (RCC); myeloid-derived suppressor cells (MDSC); tumor-associated macrophages (TAM); microvasculature; tumor-infiltrating lymphocytes (TIL); cytotoxic T lymphocytes (CTL); regulatory T cells (Tregs); immune checkpoint inhibitor (ICI); vascular endothelial growth factor (VEGF); hypoxia-inducible factor (HIF); arginase; indoleamine dioxygenase (IDO) Conflicts of interest There are no conflicts of interest.

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“…What is evidently a critical situation is that these inflammatory proteins, in particular, the CCL2 and IL-6 are brought about by the actual cancer treatments themselves (e.g., radiotherapy (16) chemotherapy (8), which in turn are then associated with tumor recurrence (17) and chemo-resistance (18,19), Inflammatory events in general, whether it be from other parts of the body such as the liver (9,20) adipose tissue in obesity or arising from viral origin tend to elevate TNF-a, IL -6 and CCL2 then becoming risk factors for the development of diverse cancers (21) aggressive tumors with advanced stage tumor grade and greater rates of mortality (22,23). Meanwhile, it is believed that drugs or natural compounds that can attenuate CCL2 and IL-6 would slow the aggressive nature of advanced cancers (24)(25)(26) to the inclusion of triple negative breast cancer (TNBC) and hormone positive breast cancers (27,28).…”

Section: Introductionmentioning

confidence: 99%

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

et al. 2020

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The lack of hormone receptors in triple negative breast cancer (TNBC) is associated with the inefficacy of anti-estrogen chemotherapies, leaving fewer options for patient treatment and higher mortality rates. Additionally, as with numerous types of inflammatory breast cancer, infiltration of tumor associated macrophages and other leukocyte sub-populations within the tumor inevitably lead to aggressive, chemo-resistant, metastatic and invasive types of cancer which escape immune surveillance. These processes are orchestrated by the release of potent cytokines, including TNFα, IL-6 and CCL2 from the stroma, tumor and immune cells within the tumor microenvironment. The present study evaluated apigenin modulating effects on the pro-inflammatory activating action of TNFα in TNBC MDA-MB-468 cells, derived from an African American woman. Initially, cell viability was determined to establish an optimal sub-lethal dose of TNFα and apigenin in MDA-MB-468 cells. Subsequently, various treatments effects were evaluated using whole transcriptomic analysis of mRNA and long intergenic non-coding RNA with Affymetrix HuGene-2.1-st human microarrays. Gene level differential expression analysis was conducted on 48,226 genes where TNFα caused significant upregulation of 53 transcripts and downregulation of 11 transcripts. The largest upward differential shift was for CCL2 [+61.86 fold change (FC); false discovery rate (FDR), P<0.0001]; which was down regulated by apigenin (to +10.71 FC vs. Control; FDR P-value <0.001), equivalent to an 83% reduction. Several TNFα deferentially upregulated transcripts were reduced by apigenin, including CXCL10, C3, PGLYRP4, IL22RA2, KMO, IL7R, ROS1, CFB, IKBKe, SLITRK6 (a checkpoint target) and MMP13. Confirmation of CCL2 experimentally induced transcript alterations was corroborated at the protein level by ELISA assays. The high level of CCL2 transcript in the cell line was comparable to that in our previous studies in MDA-MB-231 cells. The differential effects of TNFα were corroborated by ELISA, where the data revealed a >10-fold higher releasing rate of CCL2 in MDA-MB-468 cells compared with in MDA-MB-231 cells, both of which were attenuated by apigenin. The data obtained in the present study demonstrated a high level of CCL2 in MDA-MB-468 cells and a possible therapeutic role for apigenin in downregulating TNFα-mediated processes in these TNBC cells.

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Myeloid-derived suppressor cell accumulation in renal cell carcinoma is correlated with CCL2, IL-17 and IL-18 expression in blood and tumors

Cited by 35 publications

References 22 publications

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

The tumor microenvironment in renal cell cancer

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

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