Macrophages as tools and targets in cancer therapy

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(11), P. 799 - 820

Published: Aug. 16, 2022

Language: Английский

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Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells

Cell, Journal Year: 2020, Volume and Issue: 181(7), P. 1643 - 1660.e17

Published: May 28, 2020

Language: Английский

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Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance

Science Translational Medicine, Journal Year: 2020, Volume and Issue: 12(552)

Published: July 15, 2020

Macrophage subsets are dynamically altered during glioma response to radiotherapy, and their targeting delays tumor recurrence in preclinical trials.

Language: Английский

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EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Jan. 14, 2022

Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in pathophysiological processes TME remodelling various tumours.CircRNA sequencing analysis was performed explore circRNA expression profiles normal glioma tissues. The biological function novel circRNA, namely, circNEIL3, development confirmed both vitro vivo. Mechanistically, RNA pull-down, mass spectrum, immunoprecipitation (RIP), luciferase reporter, co-immunoprecipitation assays were conducted.We identified which could be cyclized EWS RNA-binding protein 1(EWSR1), upregulated tissues correlate positively progression. Functionally, we that circNEIL3 promotes tumorigenesis carcinogenic progression stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding 3) protein, known oncogenic preventing HECTD4-mediated ubiquitination. Moreover, overexpression cells drives macrophage infiltration into (TME). Finally, is packaged exosomes hnRNPA2B1 transmitted infiltrated associated macrophages (TAMs), enabling them acquire properties stabilizing turn promoting progression.This work reveals plays nonnegligible multifaceted gliomagenesis, tumour-promoting phenotypes polarization, highlighting potential prognostic biomarker therapeutic target glioma.

Language: Английский

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Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(6), P. 971 - 984

Published: May 27, 2022

Abstract Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM microenvironment during tumor evolution and standard care treatments limited. Using single-cell transcriptomics flow cytometry, we unveiled large-scale comprehensive longitudinal changes in cell composition throughout progression epidermal growth factor receptor-driven genetic mouse model. We identified subsets proinflammatory microglia developing GBMs anti-inflammatory macrophages myeloid-derived suppressors cells end-stage tumors, that parallels breakdown blood–brain barrier extensive receptor + cells. A similar relationship was found between patient biopsies low-grade glioma GBM. Temozolomide decreased accumulation suppressor cells, whereas concomitant temozolomide irradiation increased intratumoral GranzymeB CD8 T but also CD4 regulatory These results provide unbiased cellular landscape its evolutionary progression.

Language: Английский

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Intracavity generation of glioma stem cell–specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(656)

Published: Aug. 3, 2022

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating GSCs is critical for preventing postoperative this devastating disease, yet effective strategies remain elusive. Here, we report cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding cavity prevent relapse. Specifically, demonstrate CAR gene–laden nanoporter in hydrogel can introduce GSC-targeted genes into MΦ nuclei intracavity delivery generate CAR-MΦs mouse models GBM. These were able seek engulf clear by stimulating an adaptive antitumor immune response tumor microenvironment prevented inducing long-term immunity mice. In orthotopic patient–derived glioblastoma humanized model, combined treatment CD47 antibody increased frequency positive responding suppressed negative regulating cells, conferring robust tumoricidal postsurgical inhibiting Therefore, our work establishes locoregional strategy priming cancer cell–specific broad application suffering from recurrent malignancies.

Language: Английский

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Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas

Nature Cancer, Journal Year: 2021, Volume and Issue: 2(7), P. 723 - 740

Published: May 24, 2021

Abstract The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define cellular states in gliomas by longitudinal single-cell profiling demonstrate their strict control the genotype: isocitrate dehydrogenase (IDH)-mutant tumors, differentiation infiltrating is blocked, resulting an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment microenvironment, thus preventing T cell response. We IDH-dependent education to be causally related a complex re-orchestration tryptophan metabolism, activation aryl hydrocarbon receptor. further show that altered metabolism IDH-mutant maintains this axis bystander pharmacological inhibition can reverse immunosuppression. conclusion, provide evidence glioma genotype-dependent network resident recruited identify as target for immunotherapy tumors.

Language: Английский

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Macrophages and microglia: the cerberus of glioblastoma

Acta Neuropathologica Communications, Journal Year: 2021, Volume and Issue: 9(1)

Published: March 25, 2021

Abstract Glioblastoma (GBM) is the most aggressive and deadliest of primary brain tumors, characterized by malignant growth, invasion into parenchyma, resistance to therapy. GBM a heterogeneous disease high degrees both inter- intra-tumor heterogeneity. Another layer complexity arises from unique microenvironment in which develops grows. The consists neoplastic non-neoplastic cells. abundant cells are those innate immune system, called tumor-associated macrophages (TAMs). TAMs constitute up 40% tumor mass consist brain-resident microglia bone marrow-derived myeloid periphery. Although genetically stable, can change their expression profiles based upon signals that they receive cells; therefore, heterogeneity creates TAMs. By interacting with other microenvironment, promote progression. Here, we review origin, heterogeneity, functional roles In addition, discuss prospects therapeutically targeting alone or combination standard newly-emerging therapies.

Language: Английский

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IFNγ Is Critical for CAR T Cell–Mediated Myeloid Activation and Induction of Endogenous Immunity

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(9), P. 2248 - 2265

Published: April 9, 2021

Abstract Chimeric antigen receptor (CAR) T cells mediate potent antigen-specific antitumor activity; however, their indirect effects on the endogenous immune system are not well characterized. Remarkably, we demonstrate that CAR T-cell treatment of mouse syngeneic glioblastoma (GBM) activates intratumoral myeloid and induces memory responses coupled with feed-forward propagation responses. IFNγ production by responsiveness host critical for tumor landscape remodeling to promote a more activated less suppressive microenvironment. The clinical relevance these observations is supported studies showing human IL13Rα2–CAR activate patient-derived monocytes/macrophages through signaling induce generation tumor-specific in responding patient GBM. These establish therapy has potential shape microenvironment, creating context permissible eliciting immunity. Significance: Our findings highlight role productive We can resident populations immunity, emphasizing importance innate adaptive immunity solid tumors. This article highlighted In Issue feature, p. 2113

Language: Английский

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Directed evolution of adeno-associated virus for efficient gene delivery to microglia

Nature Methods, Journal Year: 2022, Volume and Issue: 19(8), P. 976 - 985

Published: July 25, 2022

Language: Английский

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