Tumour-derived CSF2/granulocyte macrophage colony stimulating factor controls myeloid cell accumulation and progression of gliomas

Sielska, Małgorzata; Przanowski, Piotr; Pasierbinska, Maria; Wojnicki, Kamil; Poleszak, Katarzyna; Wojtaś, Bartosz; Grzeganek, Dominika; Ellert-Miklaszewska, Aleksandra; Ku, Min-Chi; Kettenmann, Helmut; Kamińska, Bożena

doi:10.1038/s41416-020-0862-2

Cited by 34 publications

(26 citation statements)

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“…To evaluate the effects of these novel arginase inhibitors on glioma invasion, we performed a Matrigel invasion assay using two human glioma cell lines: U87-MG ( Figure 2C ) and LN18 ( Figure 2D ). Immortalized BV2 microglial cells, similarly to primary microglial cultures, support glioma invasion ( 38 ). In co-cultures, glioma invasion was strongly induced in the presence of BV2 microglial cells and all three arginase inhibitors significantly decreased the proportion of invading cells.…”

Section: Resultsmentioning

confidence: 99%

A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment

et al. 2021

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Glioblastomas (GBM) are the common and aggressive primary brain tumors that are incurable by conventional therapies. Immunotherapy with immune checkpoint inhibitors is not effective in GBM patients due to the highly immunosuppressive tumor microenvironment (TME) restraining the infiltration and activation of cytotoxic T cells. Clinical and experimental studies showed the upregulation of expression of the arginase 1 and 2 (ARG1 and ARG2, respectively) in murine and human GBMs. The elevated arginase activity leads to the depletion of L-arginine, an amino-acid required for the proliferation of T lymphocytes and natural killer cells. Inhibition of ARG1/2 in the TME may unblock T cell proliferation and activate effective antitumor responses. To explore the antitumor potential of ARG1/2 inhibition, we analyzed bulk and single-cell RNA sequencing (scRNA-seq) data from human and murine gliomas. We found the upregulation of ARG1/2 expression in GBMs, both in tumor cells and in tumor infiltrating microglia and monocytes/macrophages. We employed selective arginase inhibitors to evaluate if ARG1/2 inhibition in vitro and in vivo exerts the antitumor effects. A novel, selective ARG1/2 inhibitor - OAT-1746 blocked microglia-dependent invasion of U87-MG and LN18 glioma cells in a Matrigel invasion assay better than reference compounds, without affecting the cell viability. OAT-1746 effectively crossed the blood brain barrier in mice and increased arginine levels in the brains of GL261 glioma bearing mice. We evaluated its antitumor efficacy against GL261 intracranial gliomas as a monotherapy and in combination with the PD-1 inhibition. The oral treatment with OAT-1746 did not affect the immune composition of TME, it induced profound transcriptomic changes in CD11b+ cells immunosorted from tumor-bearing brains as demonstrated by RNA sequencing analyses. Treatment with OAT-1746 modified the TME resulting in reduced glioma growth and increased antitumor effects of the anti-PD-1 antibody. Our findings provide the evidence that inhibition of ARG1/2 activity in tumor cells and myeloid cells in the TME unblocks antitumor responses in myeloid cells and NK cells, and improves the efficacy of the PD-1 inhibition.

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Section: Resultsmentioning

confidence: 99%

A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment

et al. 2021

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“…CSF2 (macrophage colony stimulating factor) is overexpressed in a subset of mesenchymal GBM in association with high immune gene expression. Tumor-derived CSF2 attracts, supports the survival of, and induces the pro-tumorigenic polarization of microglia and macrophages [ 28 ].…”

Section: The Synergistic Systemmentioning

confidence: 99%

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

Chen

2021

IJMS

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The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitating glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now.

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“…Tumor-derived macrophage colony stimulating factor (M-CSF, CSF1) and granulocyte macrophage colony stimulating factor (GM-CSF, CSF2) induce microglia accumulation and activation, as well as glioma progression [62]. These factors also interact with other proinflammatory cytokines such as tumor-necrosis factor (TNF) and interleukin-1 (IL-1) [63].…”

Section: Relationship Between Inflammatory Mediators and Tamsmentioning

confidence: 99%

“…GBM derived M-CSF stimulated microglial cells to secrete insulin-like growth factor-binding protein 1 (IGFBP1) to promote angiogenesis [64]. CSF2/GM-CSF triggered microglia to enhance tumor cells infiltration capacity in human glioma [62]. Another study has demonstrated an increased migration capacity of glioma cells and resistance to apoptosis due to the presence of CSF2/GM-CSF [65].…”

Section: Relationship Between Inflammatory Mediators and Tamsmentioning

confidence: 99%

“…Moreover, the colonization of microglial cells was reduced by blocking of CSF2 signaling following CSF2/CSF2Rα antagonist administration. Furthermore, when the glioma cells deficient in CSF2 were transplanted into the mouse brain, the TAM population was diminished, and the survival rate of tumor-bearing mice improved [62]. Blocking of purinergic P2X receptor 7 (P2X7R)-dependent GM-CSF activity was shown to exert a beneficial effect against GBM [214].…”

Section: Therapeutic Potential Of Targeting Tams and Tans In Gliomamentioning

confidence: 99%

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Role of Inflammatory Mediators, Macrophages, and Neutrophils in Glioma Maintenance and Progression: Mechanistic Understanding and Potential Therapeutic Applications

Basheer

Abas

Othman

et al. 2021

Cancers

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Gliomas are the most common, highly malignant, and deadliest forms of brain tumors. These intra-cranial solid tumors are comprised of both cancerous and non-cancerous cells, which contribute to tumor development, progression, and resistance to the therapeutic regimen. A variety of soluble inflammatory mediators (e.g., cytokines, chemokines, and chemotactic factors) are secreted by these cells, which help in creating an inflammatory microenvironment and contribute to the various stages of cancer development, maintenance, and progression. The major tumor infiltrating immune cells of the tumor microenvironment include TAMs and TANs, which are either recruited peripherally or present as brain-resident macrophages (microglia) and support stroma for cancer cell expansion and invasion. These cells are highly plastic in nature and can be polarized into different phenotypes depending upon different types of stimuli. During neuroinflammation, glioma cells interact with TAMs and TANs, facilitating tumor cell proliferation, survival, and migration. Targeting inflammatory mediators along with the reprogramming of TAMs and TANs could be of great importance in glioma treatment and may delay disease progression. In addition, an inhibition of the key signaling pathways such as NF-κB, JAK/STAT, MAPK, PI3K/Akt/mTOR, and TLRs, which are activated during neuroinflammation and have an oncogenic role in glioblastoma (GBM), can exert more pronounced anti-glioma effects.

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Tumour-derived CSF2/granulocyte macrophage colony stimulating factor controls myeloid cell accumulation and progression of gliomas

Cited by 34 publications

References 50 publications

A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment

A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

Role of Inflammatory Mediators, Macrophages, and Neutrophils in Glioma Maintenance and Progression: Mechanistic Understanding and Potential Therapeutic Applications

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