The Role of Immune Cells in the Tumor Microenvironment

Whiteside, Theresa L.

doi:10.1007/0-387-26283-0_5

Cited by 90 publications

(67 citation statements)

References 81 publications

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“…20 Several studies have described the diversity of tumor escape strategies and notably, alterations in T-cell receptor signaling, suppression of T-cell responses by T regulators, suppression of natural killer activity, and decreased expression of costimulatory molecules. 21 Furthermore, some studies have shown that immune cells can also contribute to promote tumor growth. Indeed, it has been described that tumorassociated macrophages stimulate tumor angiogenesis through VEGF secretion.…”

Section: Discussionmentioning

confidence: 99%

ATP confers tumorigenic properties to dendritic cells by inducing amphiregulin secretion

Bles

Pietrantonio

Boeynaems

et al. 2010

Blood

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IntroductionThe interactions between the immune system and angiogenesis are determinant for the regulation of tumor growth. The mechanisms of these interactions are not well understood at this time. Dendritic cells (DCs) are known to play a central role in these interactions by releasing vascular endothelial growth factor-A (VEGF-A). 1,2 VEGF-A is able to induce endothelial-like differentiation of tumor-infiltrating precursors of DCs and their migration to vessels to participate to vasculogenesis. 3 VEGF-A was also reported to inhibit the function of mature DCs. 4 Immune cells such as tumor-associated macrophages and T cells were also reported to regulate angiogenesis through the secretion of potent angiogenic mediators such as angiopoietin-2 and interleukin-17 . 5,6 We demonstrated previously that ATP up-regulates the expression by monocyte-derived DCs (MoDCs) of numerous genes that may play a role in immunosuppression, in particular thrombospondin-1 and indoleamine 2,3-dioxygenase. 2,7 Some epidermal growth factor receptor (EGFR) ligands were also ATP target genes in MoDCs, in particular, amphiregulin (AREG), which was the most highly up-regulated gene. AREG is a cell type-dependent mitogenic factor that binds to ErbB1 receptor, also called EGFR. 8 AREG is implicated in tumorigenesis and angiogenesis. 9,10 Ma et al showed a reduction of the tumor mass and the intratumoral vascularization using an antisense cDNA of AREG in a breast cell line. 11 A clinical study showed that there was a significant overexpression of AREG and VEGF in primary breast cancer. 12 Kato et al showed that AREG can induce the proliferation of rat vascular smooth muscle cells and could be implicated in arterial remodeling. 13 We demonstrated here for the first time that human and mouse DCs are a source of AREG, an EGFR ligand with tumorigenic properties. Methods MiceMale 6-to 8-week-old C57BL/6 mice were obtained from Charles River Laboratories. All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the US National Institutes of Health (NIH) and were approved by the Comission d'Ethique et du Bien-Etre Animal (CEBEA) ethical committee. ReagentsATP, adenosine 5Ј-O-(3-thiotriphosphate; ATP␥S), UTP, prostaglandin E2 (PGE 2 ), adenosine (Ado), NECA (5Ј-(N-ethylcarboxamido)adenosine), suramin, MRS1754, and lipopolysaccharide (LPS) were obtained from Sigma-Aldrich. Monoclonal anti-human and anti-mouse AREG blocking antibodies were purchased at R&D Systems. Preparation of human monocyte-derived DCsPeripheral blood mononuclear cells were isolated from leukocyte-enriched buffy coats of healthy volunteer donors by standard density gradient centrifugation using Lymphoprep solution from Nycomed. Mononuclear cells (2.5 ϫ 10 8 ) were allowed to adhere during 1 hour and 30 minutes at 37°C at 5% CO 2 in 75-cm 2 cell culture flasks. Nonadherent cells were removed, and adherent cells were cultured in 15 mL of culture medium For personal use only. on April 4, 2019. by guest ...

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Section: Discussionmentioning

confidence: 99%

ATP confers tumorigenic properties to dendritic cells by inducing amphiregulin secretion

Bles

Pietrantonio

Boeynaems

et al. 2010

Blood

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“…Although being detrimental to tumour cells, the EBV-DNA load in hepatocellular carcinoma was found to be 1000-fold higher than in peripheral blood mononuclear cells (Sugawara et al, 2000;Tamada and Chen, 2006). It appears possible that the tumour controls and inactivates these cells, as described for other infiltrating leukocytes (De Visser et al, 2006;Whiteside, 2006).…”

Section: Discussionmentioning

confidence: 95%

“…They are, therefore, capable of remodelling connective tissue, stimulate invasion, migration, and growth of tumour cells, and induce neoangiogenesis (Dubuisson et al, 2000;Monvoisin et al, 2002). Furthermore, important cellular components of the tumour microenvironment are various types of leukocytes, including dendritic cells, natural killer cells, and tumour-associated macrophages (Robinson and Coussens, 2005;De Visser et al, 2006;Whiteside, 2006). Their interaction with tumour cells often results in immunotolerance through reduced immunogenicitiy of the tumour and incapacitation of immune cells.…”

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confidence: 99%

“…Their interaction with tumour cells often results in immunotolerance through reduced immunogenicitiy of the tumour and incapacitation of immune cells. The immune cells may even increase the potential of cancer cells to progress, proliferate, and metastasise, that is, the tumourassociated macrophages release metalloproteinases for local tissue destruction and interleukin (IL)-6 and IL-8 for endothelial cell invasion into the tumour (De Visser et al, 2006;Whiteside, 2006). In summary, there is strong evidence that the various mesenchymal cell types in the (pre)malignant tissue undergo a multiplicity of deviations, crucial for cancer formation, progression, and maintenance.…”

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New cellular tools reveal complex epithelial–mesenchymal interactions in hepatocarcinogenesis

et al. 2008

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To enable detailed analyses of cell interactions in tumour development, new epithelial and mesenchymal cell lines were established from human hepatocellular carcinoma by spontaneous outgrowth in culture. We obtained several hepatocarcinoma (HCC)-, B-lymphoblastoid (BLC)-, and myofibroblastoid (MF)-lines from seven cases. In-depth characterisation included cell kinetics, genotype, tumourigenicity, expression of cell-type specific markers, and proteome patterns. Many functions of the cells of origin were found to be preserved. We studied the impact of the mesenchymal lines on hepatocarcinogenesis by in vitro assays. BLC-and MF-supernatants strongly increased the DNA replication of premalignant hepatocytes. The stimulation by MF-lines was mainly attributed to HGF secretion. In HCC-cells, MF-supernatant had only minor effects on cell growth but enhanced migration. MF-lines also stimulated neoangiogenesis through vEGF release. BLC-supernatant dramatically induced death of HCC-cells, which could be largely abrogated by preincubating the supernatant with TNFb-antiserum. Thus, the new cell lines reveal stage-specific stimulatory and inhibitory interactions between mesenchymal and epithelial tumour cells. In conclusion, the new cell lines provide unique tools to analyse essential components of the complex interplay between the microenvironment and the developing liver cancer, and to identify factors affecting proliferation, migration and death of tumour cells, neoangiogenesis, and outgrowth of additional malignancy.

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“…Yet, solid tumors are mostly recognized as "self" and they do not evoke efficient immune responses capable of eradicating tumors [148,149]. In contrast, it was found that these cells are actively recruited to neoplastic tissues by tumor cells and that high numbers of several types of leukocytes are associated with tumor progression [38,[150][151][152]. Nevertheless in some cancers, the presence of leukocytes is associated with a favorable prognosis [153].…”

Section: Leukocytesmentioning

confidence: 99%

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

Schwendener¹,

Mete²

2013

Frontiers in Clinical Drug Research - Anti-Cancer Agents

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Solid tumors grow within a complex microenvironment composed of diverse cell types such as fibroblasts, endothelial cells, mast cells, macrophages and immune cells that are attracted by tumor cell derived factors and embedded in an extracellular matrix. Molecular and cellular interactions between epithelial cells and cells surrounding the tumor stroma promote growth, invasion and spread of tumors. To delay or impede tumor growth, the tumor microenvironment (TME) is increasingly being explored as a potential therapeutic target for which novel strategies are developed. lt;/pgt;lt;pgt; This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed. This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed.

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The Role of Immune Cells in the Tumor Microenvironment

Cited by 90 publications

References 81 publications

ATP confers tumorigenic properties to dendritic cells by inducing amphiregulin secretion

ATP confers tumorigenic properties to dendritic cells by inducing amphiregulin secretion

New cellular tools reveal complex epithelial–mesenchymal interactions in hepatocarcinogenesis

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

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