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dc.contributor.authorPoli, Aurélieen_US
dc.contributor.authorWang, Jianen_US
dc.contributor.authorDomingues, Oliviaen_US
dc.contributor.authorPlanagumà, Jesúsen_US
dc.contributor.authorYan, Taoen_US
dc.contributor.authorRygh, Cecilie Brekkeen_US
dc.contributor.authorSkaftnesmo, Kai Oveen_US
dc.contributor.authorThorsen, Frits Alanen_US
dc.contributor.authorMcCormack, Emmeten_US
dc.contributor.authorHentges, Françoisen_US
dc.contributor.authorPedersen, Paal-Henningen_US
dc.contributor.authorZimmer, Jacquesen_US
dc.contributor.authorEnger, Per Øyvinden_US
dc.contributor.authorChekenya, Marthaen_US
dc.description.abstractGlioblastoma (GBM) is the most malignant brain tumor where patients’ survival is only 14.6 months, despite multimodal therapy with debulking surgery, concurrent chemotherapy and radiotherapy. There is an urgent, unmet need for novel, effective therapeutic strategies for this devastating disease. Although several immunotherapies are under development for the treatment of GBM patients, the use of natural killer (NK) cells is still marginal despite this being a promising approach to treat cancer. In regard of our knowledge on the role of NG2/CSPG4 in promoting GBM aggressiveness we investigated the potential of an innovative immunotherapeutic strategy combining mAb9.2.27 against NG2/CSPG4 and NK cells in preclinical animal models of GBM. Multiple immune escape mechanisms maintain the tumor microenvironment in an anti-inflammatory state to promote tumor growth, however, the distinct roles of resident microglia versus recruited macrophages is not elucidated. We hypothesized that exploiting the cytokine release capabilities of activated NK cells to reverse the anti-inflammatory axis combined with mAb9.2.27 targeting the NG2/CSPG4 may favor tumor destruction by editing pro-GBM immune responses. Combination treatment with NK+mAb9.2.27 diminished tumor growth that was associated with reduced tumor proliferation, increased cellular apoptosis and prolonged survival compared to vehicle and monotherapy controls. The therapeutic efficacy was mediated by recruitment of CCR2low macrophages into the tumor microenvironment, increased ED1 and MHC class II expression on microglia that might render them competent for GBM antigen presentation, as well as elevated IFN-γ and TNF-α levels in the cerebrospinal fluid compared to controls. Depletion of systemic macrophages by liposome-encapsulated clodronate decreased the CCR2low macrophages recruited to the brain and abolished the beneficial outcomes. Moreover, mAb9.2.27 reversed tumor-promoting effects of patient-derived tumor-associated macrophage/ microglia (TAM) ex vivo. Taken together, these findings indicate that NK+mAb9.2.27 treatment may be an amenable therapeutic strategy to treat NG2/CSPG4 expressing GBMs. We provide a novel conceptual approach of combination immunotherapy for glioblastoma. The results traverse beyond the elucidation of NG2/CSPG4 as a therapeutic target, but demonstrate a proof of concept that this antibody may hold potential for the treatment of GBM by activation of tumor infiltrated microglia/macrophages.en_US
dc.publisherImpact Journalseng
dc.relation.ispartof<a href="" target="blank">Targeting the anti-inflammatory interplay promoting glioblastoma progression with combined natural killer cells and mab9.2.27 against NG2/CSPG4</a>eng
dc.rightsAttribution CC BYeng
dc.subjectNK cellseng
dc.titleTargeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survivalen_US
dc.typePeer reviewed
dc.typeJournal article

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