The Sabotaging Role of Myeloid Cells in Anti-Angiogenic Therapy: Coordination of Angiogenesis and Immune Suppression by Hypoxia

BackgroundAlthough gliomas are confined to the central nervous system, their negative influence over the immune system extends to peripheral circulation. The immune suppression exerted by myeloid cells can affect both response to therapy and disease outcome. We analyzed the expansion of several myeloid parameters in the blood of low- and high-grade gliomas and assessed their relevance as biomarkers of disease and clinical outcome.MethodsPeripheral blood was obtained from 134 low- and high-grade glioma patients. CD14+, CD14+/p-STAT3+, CD14+/PD-L1+, CD15+ cells and four myeloid-derived suppressor cell (MDSC) subsets, were evaluated by flow cytometry. Arginase-1 (ARG1) quantity and activity was determined in the plasma. Multivariable logistic regression model was used to obtain a diagnostic score to discriminate glioma patients from healthy controls and between each glioma grade. A glioblastoma prognostic model was determined by multiple Cox regression using clinical and myeloid parameters.ResultsChanges in myeloid parameters associated with immune suppression allowed to define a diagnostic score calculating the risk of being a glioma patient. The same parameters, together with age, permit to calculate the risk score in differentiating each glioma grade. A prognostic model for glioblastoma patients stemmed out from a Cox multiple analysis, highlighting the role of MDSC, p-STAT3, and ARG1 activity together with clinical parameters in predicting patient’s outcome.ConclusionsThis work emphasizes the role of systemic immune suppression carried out by myeloid cells in gliomas. The identification of biomarkers associated with immune landscape, diagnosis, and outcome of glioblastoma patients lays the ground for their clinical use.

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A liquid biopsy-based approach identifies myeloid cells, STAT3 and arginase-1 as predictors of glioma risk score and patients' survival

10.21203/rs.3.rs-895672/v1 ◽

2021 ◽

Author(s):

Paola Del Bianco ◽

Laura Pinton ◽

Sara Magri ◽

Stefania Canè ◽

Elena Masetto ◽

...

Keyword(s):

Risk Score ◽

Immune Suppression ◽

Prognostic Model ◽

Cox Regression ◽

Myeloid Cells ◽

Response To Therapy ◽

High Grade ◽

Diagnostic Score ◽

Arginase 1

Abstract Background Although gliomas are strictly confined to the central nervous system, their negative influence over the immune system can extend to peripheral circulation. The immune suppression exerted by myeloid cells is capable of affecting both response to therapy and disease outcome. Here we analyzed the expansion of several myeloid parameters in the blood of low- and high-grade gliomas and assessed their relevance as biomarkers of disease and clinical outcome. Methods Peripheral blood was obtained from 134 low- and high-grade glioma patients before surgery and treatment. Myeloid cell subsets such as total CD14+, CD14+/p-STAT3+, CD14+/PD-L1+, CD15+ cells and 4 myeloid derived suppressor cell (MDSC) subsets, were evaluated by multiparametric flow cytometry. Arginase-1 (ARG1) quantity and activity was determined in the plasma. Principal component analysis was performed to define correlations between myeloid markers. Multivariable logistic regression model was used to obtain a diagnostic score to discriminate glioma patients from healthy controls, and between each glioma grade. A glioblastoma prognostic model was determined by multiple Cox regression using clinical and myeloid parameters. Results In the blood of glioma patients, changes in myeloid parameters associated with immune suppression were identified and allowed us to define a diagnostic score calculating the risk of being a glioma patient, that included CD15+ cells, MDSC1, MDSC3, p-STAT3 and ARG1 activity. Of note, the same parameters, together with age, can also be used to calculate the risk score in differentiating each glioma grade. Finally, a prognostic model for glioblastoma patients stemmed out from a Cox multiple analysis, highlighting the role of MDSC, p-STAT3 and ARG1 activity together with clinical parameters in predicting the patient outcome. Conclusions This work emphasizes the role of systemic immune suppression carried out by myeloid cells in gliomas. The identification of biomarkers associated with immune landscape, diagnosis and outcome of glioblastoma patients lays the ground for their clinical use for stratification and follow up.

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Overview on the Different Patterns of Tumor Vascularization

Cells ◽

10.3390/cells10030639 ◽

2021 ◽

Vol 10 (3) ◽

pp. 639

Author(s):

Domenico Ribatti ◽

Francesco Pezzella

Keyword(s):

Vasculogenic Mimicry ◽

Endothelial Cell Proliferation ◽

Published Data ◽

Alternative Mechanism ◽

Tumor Vascularization ◽

Angiogenic Therapy ◽

Physiological Processes ◽

Inhibition Of Angiogenesis ◽

Therapeutic Development

Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.

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Role of innate immunity and myeloid cells in susceptibility to allergic disease

Annals of the New York Academy of Sciences ◽

10.1111/nyas.14654 ◽

2021 ◽

Author(s):

Justine C. Noel ◽

M. Cecilia Berin

Keyword(s):

Innate Immunity ◽

Allergic Disease ◽

Myeloid Cells

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Myeloid HIF1α Is Involved in the Extent of Orthodontically Induced Tooth Movement

Biomedicines ◽

10.3390/biomedicines9070796 ◽

2021 ◽

Vol 9 (7) ◽

pp. 796

Author(s):

Christian Kirschneck ◽

Nadine Straßmair ◽

Fabian Cieplik ◽

Eva Paddenberg ◽

Jonathan Jantsch ◽

...

Keyword(s):

Bone Density ◽

Periodontal Ligament ◽

Tooth Movement ◽

Hypoxia Inducible Factor ◽

Myeloid Cells ◽

Orthodontic Tooth Movement ◽

Periodontal Ligament Fibroblasts ◽

Expression Of Genes ◽

Periodontal Bone Loss

During orthodontic tooth movement, transcription factor hypoxia-inducible factor 1α (HIF1α) is stabilised in the periodontal ligament. While HIF1α in periodontal ligament fibroblasts can be stabilised by mechanical compression, in macrophages pressure application alone is not sufficient to stabilise HIF1α. The present study was conducted to investigate the role of myeloid HIF1α during orthodontic tooth movement. Orthodontic tooth movement was performed in wildtype and Hif1αΔmyel mice lacking HIF1α expression in myeloid cells. Subsequently, µCT images were obtained to determine periodontal bone loss, extent of orthodontic tooth movement and bone density. RNA was isolated from the periodontal ligament of the control side and the orthodontically treated side, and the expression of genes involved in bone remodelling was investigated. The extent of tooth movement was increased in Hif1αΔmyel mice. This may be due to the lower bone density of the Hif1αΔmyel mice. Deletion of myeloid Hif1α was associated with increased expression of Ctsk and Acp5, while both Rankl and its decoy receptor Opg were increased. HIF1α from myeloid cells thus appears to play a regulatory role in orthodontic tooth movement.

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PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

Cancers ◽

10.3390/cancers13020164 ◽

2021 ◽

Vol 13 (2) ◽

pp. 164

Author(s):

Federica Costa ◽

Valentina Marchica ◽

Paola Storti ◽

Fabio Malavasi ◽

Nicola Giuliani

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Survival ◽

Immune Suppression ◽

Metabolic Pathways ◽

Therapeutic Strategy ◽

Myeloma Cell ◽

Immune Microenvironment ◽

Potential Use

The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients.

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Immature myeloid cells and cancer-associated immune suppression

Cancer Immunology Immunotherapy ◽

10.1007/s00262-002-0280-8 ◽

2002 ◽

Vol 51 (6) ◽

pp. 293-298 ◽

Cited By ~ 218

Author(s):

Sergei Kusmartsev ◽

Dmitry Gabrilovich

Keyword(s):

Immune Suppression ◽

Myeloid Cells ◽

Immature Myeloid Cells

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Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.610661 ◽

2020 ◽

Vol 8 ◽

Author(s):

Ye Zeng ◽

Bingmei M. Fu

Keyword(s):

Vasculogenic Mimicry ◽

Resistance Mechanisms ◽

Vascular Endothelial ◽

Beneficial Effects ◽

Sprouting Angiogenesis ◽

Intussusceptive Angiogenesis ◽

Angiogenic Therapy ◽

Tumor Neovascularization ◽

Endothelial Growth Factor

Anti-angiogenic therapies (AATs) have been widely used for cancer treatment. But the beneficial effects of AATs are short, because AAT-induced tumor revascularization facilitates the tumor relapse. In this mini-review, we described different forms of tumor neovascularization and revascularization including sprouting angiogenesis, vessel co-option, intussusceptive angiogenesis, and vasculogenic mimicry, all of which are closely mediated by vascular endothelial growth factor (VEGF), angiopoietins, matrix metalloproteinases, and exosomes. We also summarized the current findings for the resistance mechanisms of AATs including enhancement in pro-angiogenic cytokines, heterogeneity in tumor-associated endothelial cells (ECs), crosstalk between tumor cells and ECs, masking of extracellular vesicles, matrix stiffness and contributions from fibroblasts, macrophages and adipocytes in the tumor microenvironment. We highlighted the revascularization following AATs, particularly the role of exosome stimulating factors such as hypoxia and miRNA, and that of exosomal cargos such as cytokines, miRNAs, lncRNAs, and circRNAs from the tumor ECs in angiogenesis and revascularization. Finally, we proposed that renormalization of tumor ECs would be a more efficient cancer therapy than the current AATs.

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