Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis

Wang, Ying; Liu, Tao; Yang, Ning; Xu, Shuo; Li, Xingang; Wang, Donghai

doi:10.3892/or.2016.5171

Cited by 50 publications

(48 citation statements)

References 35 publications

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“…25 However, data indicating potential tumorsupportive effects of CCR5 have appeared recently. These include the enhancement of the invasive properties of pancreatic, 26 glioma 27 or basal breast 28 cancer cells in vitro, the promotion of tumor cell proliferation 15,29 or the support of tumor growth and metastasis formation in xenografts models of colorectal 30 or gastric cancer. 31 Data from immunohistological analyses in primary CRC have indicated a relationship between stage and the CCR5 expression on tumor cells.…”

Section: Introductionmentioning

confidence: 99%

CCR5 status and metastatic progression in colorectal cancer

et al. 2019

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Multiple reports have highlighted the importance of the local immunological cellular composition (i.e. the density of effector T cells and macrophage polarization state) in predicting clinical outcome in advanced metastatic stage of colorectal cancer. However, in spite of the general association between a high effector T cell density and improved outcome, our recent work has revealed a specific lymphocyte-driven cancer cell-supporting signal. Indeed, lymphocyte-derived CCL5 supports CCR5-positive tumor cell proliferation and thereby fosters tumor growth in metastatic liver lesions. Upon systematic analysis of CCR5 expression by tumor cells using immunohistochemistry, we observed that the intensity of CCR5 increases with primary tumor size and peaks in T4 tumors. In liver metastases however, though CCR5 expression intensity is globally heightened compared to primary tumors, alterations in the expression patterns appear, leading to "patchiness" of the stain. CCR5 patchiness is, therefore, a signature of liver metastases in our cohort (n = 97 specimens) and relates to globally decreased expression intensity, but does not influence the extent of the response to CCR5 inhibitor Maraviroc in patients. Moreover, CCR5 patchiness relates to a poor immune landscape characterized by a low cytotoxic-to-regulatory T cell ratio at the invasive margin and enriched cellular and molecular markers of macrophage M2 polarization. Finally, because higher numbers of PD-1-and CTLA-4-positive cells surround tumors with patchy CCR5 expression, one can speculate that these tumors potentially respond to immune checkpoint blockade. This hypothesis is corroborated by the prolonged disease-free survival and disease-specific survival observed in patients with low gene expression of CCR5 in metastases from two publically available cohorts. These observations highlight the complex role of the CCL5-CCR5 axis in CRC metastatic progression and warrant further investigations.

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Section: Introductionmentioning

confidence: 99%

CCR5 status and metastatic progression in colorectal cancer

et al. 2019

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“…These glioma cells activate migratory processes in an attempt to escape hypoxia and to reach oxygen-rich areas adjacent to blood vessels (18). Some of the pro-migratory and pro-invasive factors produced or activated in response to hypoxic conditions include: metalloproteases like MMP-9, A Disintegrin, and Metalloproteinase (ADAM)-17 (19,20); galectins (21); epithelial to mesenchymal transition (EMT) transcriptional regulators like SLUG and SNAIL and the zinc-finger E-Boxbinding homeobox proteins ZEB-1 and ZEB-2 (22,23); and CXCR4 and CXCR7, the latter mediating glioma cell migration toward stromal-derived factor (SDF)-1a/CXCL12 (24,25).…”

Section: Hypoxiamentioning

confidence: 99%

Molecular Mechanisms of Glioma Cell Motility

et al. 2017

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Gliomas are the most common intracranial tumors in humans. The most malignant among these tumors is glioblastoma (GBM), with an incidence of 3-5 out of 100,000 persons in Western countries. GBM arises either de novo (primary GBM) or develops from a lower grade glioma (secondary GBM). The prognosis is poor. GBMs are lethal tumors and even optimal surgical resection, followed by chemotherapy and irradiation, results in a median survival of about 12-15 months. One characteristic that is responsible for GBM malignancy, and its worse prognosis, is the highly infiltrative growth of GBM cells into the healthy brain. GBM cell migration and invasion is a very complex process that is regulated by several factors, which include changes in the migrating cell itself as well as the tumor microenvironment. This chapter provides an overview of routes of invasion of glioma cells, the signaling pathways that drive glioma cell motility, and the processes through which glioma cells modulate their surrounding environment.

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“…This work is under further investigation in a phase I clinical trial (NCT03602157). Expressed on CD4+ but not on mature CD8+ T cells, CCR4 could be a versatile, albeit promiscuous, strategy as it recognizes the chemokines CCL2, CCL4, CCL5, CCL17, and CCL21, which have all been associated with glioma . Despite this connection, engineered chemokine receptors have not specifically been evaluated in CAR T cells for the treatment of brain tumors.…”

Section: Getting Cars To Go: Car T Cell Trafficking To Brain Tumorsmentioning

confidence: 99%

“…Engineering CCL17, and CCL21, which have all been associated with glioma. [208][209][210][211] Despite this connection, engineered chemokine receptors have not specifically been evaluated in CAR T cells for the treatment of brain tumors. CCL2 is also produced by the glioma microenvironment to recruit both Treg and myeloid-derived suppressor cells.…”

Section: Engineering Car T Cells For Improved Tumor Tropismmentioning

confidence: 99%

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

174

161

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Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

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Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis

Cited by 50 publications

References 35 publications

CCR5 status and metastatic progression in colorectal cancer

CCR5 status and metastatic progression in colorectal cancer

Molecular Mechanisms of Glioma Cell Motility

CAR T cells for brain tumors: Lessons learned and road ahead

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