Macrophage-derived IL-1β and TNF-α regulate arginine metabolism in neuroblastoma

© 2018 American Association for Cancer Research. Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating monocytes to an M1-macrophage phenotype, which released IL1b and TNFa in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1b and TNFa established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signaling in neuroblastoma and neural crest-derived cells. Proteomic analysis revealed that enrichment of IL1b and TNFa in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited

Cellular Senescence in paediatric diffuse high-grade glioma: from mechanism to therapeutic opportunities

Paediatric-type Diffuse high-grade gliomas (PDHGGs) are aggressive brain tumours that are treated palliatively with radiotherapy. Radiation therapy can induce cellular senescence, a state where cells cease to divide, it can also create a therapeutic vulnerability in tumour cells. We investigated this hypothesis by combining in vitro and in vivo approaches with transcriptomics to understand the impact of radiation-induced senescence on PDHGGs and the vulnerability of these cells to senolytic agents. We found that radiation-induced senescence in PDHGGs creates a unique therapeutic opportunity that can be exploited using Navitoclax, a small molecule inhibitor of Bcl-2/ Bcl-xL. We demonstrated that Navitoclax in synergy with radiation induces cell death in PDHGGs both in vitro and in vivo, resulting in a significant improvement in survival in preclinical models. We further used single cell transcriptomic and immunohistochemical data identifying a distinct subpopulation of macrophages that are senescent and express high levels of senescence markers in human PDHGGs. To validate our findings, we utilised the p16-FDR mouse model combining with a K27M-driven glioma, GEMM that closely mimics human PDHGGs. Using this model, we identified further evidence of a sub-population of macrophage expressing a number of senescent markers. Overall, our study sheds light on the role of senescence in PDHGGs and presents a promising therapeutic strategy for this deadly cancer. Our integrated approach that combines preclinical models, transcriptomic data, and immunohistochemical analyses can provide a framework for targeting senescent cells in PDHGGs

Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma:a retrospective, multicentre, cohort study of 3,679 patients with long-term imaging surveillance

Background Radiotherapy is a valuable treatment in the management algorithm of pituitary adenomas and craniopharyngiomas. However, the risk of second brain tumour following radiotherapy is a major concern. We assessed this risk using non-irradiated patients with the same primary pathology and imaging surveillance as controls.Methods In this multicentre, retrospective cohort study, 4292 patients with pituitary adenoma or craniopharyngioma were identified from departmental registries at six adult endocrine centres (Birmingham, Oxford, Leeds, Leicester, and Bristol, UK and Ferrara, Italy). Patients with insufficient clinical data, known genetic predisposition to or history of brain tumour before study entry (n=532), and recipients of proton beam or stereotactic radiotherapy (n=81) were excluded. Data were analysed for 996 patients exposed to 2-dimensional radiotherapy, 3-dimensional conformal radiotherapy, or intensity-modulated radiotherapy, and compared with 2683 controls.Findings Over 45 246 patient-years, second brain tumours were reported in 61 patients (seven malignant [five radiotherapy, two controls], 54 benign [25 radiotherapy, 29 controls]). Radiotherapy exposure and older age at pituitary tumour detection were associated with increased risk of second brain tumour. Rate ratio for irradiated patients was 2.18 (95% CI 1.31-3.62, p<0.0001). Cumulative probability of second brain tumour was 4% for the irradiated and 2.1% for the controls at 20 years.Interpretation Irradiated adults with pituitary adenoma or craniopharyngioma are at increased risk of second brain tumours, although this risk is considerably lower than previously reported in studies using general population controls with no imaging surveillance. Our data clarify an important clinical question and guide clinicians when counselling patients with pituitary adenoma or craniopharyngioma on the risks and benefits of radiotherapy. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd

Macrophage IL-1B and TNF-a create an immune-metabolic loop regulating Arginase2 in neuroblastoma

International audienceNeuroblastoma is the most common solid tumour of childhood, yet the prognosis for high risk disease remains poor. We demonstrate that arginine metabolism via Arginase 2 (ARG2) drives neuroblastoma cell proliferation. Targeting arginine metabolism by blocking Cationic Amino Acid Transporter 1 (CAT-1) dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated-recombinant arginase BCT-100 significantly delays tumour development and prolongs murine survival. Tumour cells polarise infiltrating monocytes to a M1- macrophage phenotype, which release IL-1 and TNF-a in an RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. Il-1 and TNF- signal-back to upregulate ARG2 expression via p38 and Extracellular regulated kinases 1/2 (ERK1/2) signalling in neuroblastoma and neural crest-derived cells. Proteomic analysis reveal Stage IV human tumour microenvironments are enriched in IL-1 and TNF-a, which is associated with a worse prognosis. Thus we describe an immune-metabolic regulatory loop between tumour cells and infiltrating myeloid cells regulating ARG2, which could clinically exploited. Statement of significance: Neuroblastoma polarised macrophages released IL-1and TNF which signal back to regulate Arginase2 in tumour cells and drive their proliferatio