Combining NK cells and mAb9.2.27 to combat NG2-dependent and anti-inflammatory signals in glioblastoma

Kmiecik, Justyna; Navarro, Andrea Gras; Poli, Aurélie; Planagumà, Jesús; Zimmer, Jacques; Chekenya, Martha

doi:10.4161/onci.27185

Cited by 27 publications

(27 citation statements)

References 10 publications

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“…Having previously shown that NK cells are involved in mediating the effect of EE on glioma progression ( Garofalo et al, 2015 ), we now investigated the role of NK cells in EE-induced phenotypic switch of myeloid cells. Other studies also have correlated microglia/macrophage activation state with NK cell activity ( Kmiecik et al, 2014 ). We demonstrate that NK cell depletion completely abolishes the effect of EE on pro- and anti-inflammatory gene expression in CD11b + cells.…”

Section: Discussionmentioning

confidence: 99%

Environmental stimuli shape microglial plasticity in glioma

Garofalo

Porzia

Mainiero

et al. 2017

eLife

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In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, which contribute to tumor growth and to maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, the branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted. Modulation of gene expression depends on interferon-(IFN)-γ produced by natural killer (NK) cells. This modulation disappears in mice depleted of NK cells or lacking IFN-γ, and was mimicked by exogenous interleukin-15 (IL-15). Further, we describe a key role for brain-derived neurotrophic factor (BDNF) that is produced in the brain of mice housed in EE, in mediating the expression of IL-15 in CD11b+ cells. These data define novel mechanisms linking environmental cues to the acquisition of a pro-inflammatory, anti-tumor microenvironment in mouse brain.

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Section: Discussionmentioning

confidence: 99%

Environmental stimuli shape microglial plasticity in glioma

Garofalo

Porzia

Mainiero

et al. 2017

eLife

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“…Targeting NG2/CSPG4 with mAb 9.2.27 and activated natural killer cells inhibited the tumor growth and improved the survival of GB-bearing animals with the establishment of a pro-inflammatory microenvironment [ 110 , 111 ]. Similar effects were obtained by miR-129-2 [ 34 ].…”

Section: Ng2/cspg4 In the Treatment Of Gliomasmentioning

confidence: 99%

The Significance of Chondroitin Sulfate Proteoglycan 4 (CSPG4) in Human Gliomas

Schiffer

Mellai

Boldorini

et al. 2018

IJMS

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Neuron glial antigen 2 (NG2) is a chondroitin sulphate proteoglycan 4 (CSPG4) that occurs in developing and adult central nervous systems (CNSs) as a marker of oligodendrocyte precursor cells (OPCs) together with platelet-derived growth factor receptor α (PDGFRα). It behaves variably in different pathological conditions, and is possibly involved in the origin and progression of human gliomas. In the latter, NG2/CSPG4 induces cell proliferation and migration, is highly expressed in pericytes, and plays a role in neoangiogenesis. NG2/CSPG4 expression has been demonstrated in oligodendrogliomas, astrocytomas, and glioblastomas (GB), and it correlates with malignancy. In rat tumors transplacentally induced by N-ethyl-N-nitrosourea (ENU), NG2/CSPG4 expression correlates with PDGFRα, Olig2, Sox10, and Nkx2.2, and with new vessel formation. In this review, we attempt to summarize the normal and pathogenic functions of NG2/CSPG4, as well as its potential as a therapeutic target.

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“…We showed that combination treatment of adoptively transferred NK cells with mAb9.2.27 against NG2/CSPG4 in preclinical models of GBM induced synergistic therapeutic effects through TNF-α, a IFN-γ release, diminished IL-10, IL-6, and IL-1α. Combination NK cells + mAb9.2.27 induced potent ADCC mediated by Fcγ-IIR on microglia/macrophages that resulted in prolonged survival ( 158 , 159 ). mAb9.2.27 could not induce ADCC by NK cells proper , likely because of its IgG2a isotype, known to engage weakly the Fcγ-RIII on NK cells.…”

Section: Antibody-dependent Cellular Cytotoxicitymentioning

confidence: 99%

Therapeutic Potential and Challenges of Natural Killer Cells in Treatment of Solid Tumors

2015

Self Cite

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Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.

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Combining NK cells and mAb9.2.27 to combat NG2-dependent and anti-inflammatory signals in glioblastoma

Cited by 27 publications

References 10 publications

Environmental stimuli shape microglial plasticity in glioma

Environmental stimuli shape microglial plasticity in glioma

The Significance of Chondroitin Sulfate Proteoglycan 4 (CSPG4) in Human Gliomas

Therapeutic Potential and Challenges of Natural Killer Cells in Treatment of Solid Tumors

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