Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio

Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors

MRI-Based Deep Learning Tools for MGMT Promoter Methylation Detection: A Thorough Evaluation

Glioblastoma is the most aggressive primary brain tumor, which almost systematically relapses despite surgery (when possible) followed by radio-chemotherapy temozolomide-based treatment. Upon relapse, one option for treatment is another chemotherapy, lomustine. The efficacy of these chemotherapy regimens depends on the methylation of a specific gene promoter known as MGMT, which is the main prognosis factor for glioblastoma. Knowing this biomarker is a key issue for the clinician to personalize and adapt treatment to the patient at primary diagnosis for elderly patients, in particular, and also upon relapse. The association between MRI-derived information and the prediction of MGMT promoter status has been discussed in many studies, and some, more recently, have proposed the use of deep learning algorithms on multimodal scans to extract this information, but they have failed to reach a consensus. Therefore, in this work, beyond the classical performance figures usually displayed, we seek to compute confidence scores to see if a clinical application of such methods can be seriously considered. The systematic approach carried out, using different input configurations and algorithms as well as the exact methylation percentage, led to the following conclusion: current deep learning methods are unable to determine MGMT promoter methylation from MRI data

Evaluation of Lignocellulosic Wastewater Valorization with the Oleaginous Yeasts <i>R. kratochvilovae</i> EXF7516 and <i>C. oleaginosum</i> ATCC 20509

During the conversion of lignocellulose, phenolic wastewaters are generated. Therefore, researchers have investigated wastewater valorization processes in which these pollutants are converted to chemicals, i.e., lipids. However, wastewaters are lean feedstocks, so these valorization processes in research typically require the addition of large quantities of sugars and sterilization, which increase costs. This paper investigates a repeated batch fermentation strategy with Rhodotorula kratochvilovae EXF7516 and Cutaneotrichosporon oleaginosum ATCC 20509, without these requirements. The pollutant removal and its conversion to microbial oil were evaluated. Because of the presence of non-monomeric substrates, the ligninolytic enzyme activity was also investigated. The repeated batch fermentation strategy was successful, as more lipids accumulated every cycle, up to a total of 5.4 g/L (23% cell dry weight). In addition, the yeasts consumed up to 87% of monomeric substrates, i.e., sugars, aromatics, and organics acids, and up to 23% of non-monomeric substrates, i.e., partially degraded xylan, lignin, cellulose. Interestingly, lipid production was only observed during the harvest phase of each cycle, as the cells experienced stress, possibly due to oxygen limitation. This work presents the first results on the feasibility of valorizing non-sterilized lignocellulosic wastewater with R. kratochvilovae and C. oleaginosum using a cost-effective repeated batch strategy

Low-grade epilepsy-associated neuroepithelial tumours with a prominent oligodendroglioma-like component: the diagnostic challenges

International audienceAIM: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low-grade epilepsy-associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma-like component, in order to classify them according to the 2021 WHO classification of CNS tumours. MATERIAL AND METHODS: Centralized pathological examination was performed as well as targeted molecular analysis of BRAF and FGFR1 by multiplexed digital PCR (mdPCR). DNA-methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done. RESULTS: We first reclassified our cohort into 3 groups: ganglioglioma (GG, n=14), dysembryoplastic neuroepithelial tumours (DNT, n=19) and glioneuronal tumours/paediatric-type low grade glioma not otherwise specified (GNT/PLGG NOS, n=39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or NTRK2 in 9/25 cases. DNA-methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed 2 clusters: cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG-DNT methylation class (MC), with CD34 negativity and FGRF1 alterations; cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG-GG MC methylation class, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low grade neuroepithelial tumour of the young belonged to cluster 2 whereas diffuse LGG MAPK pathway-altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma-like component. CONCLUSIONS: Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma-like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinico-pathological relevance of the four types recognized by the WHO CNS5 within this spectrum of tumours is questionable

Two novel tumours with NTRK2 fusion in the methylation class of extraventricular neurocytomas, including one intraventricular

International audienceWe report here about two novel tumours classified as extraventricular neurocytomas (EVN) using DNA-methylation profiling, associated with NTRK2 fusions instead of the usual FGFR1 alterations so far attributed to this tumoural entity. We present the second detailed case of an intraventricular presentation in the MC EVN. Our findings broaden the spectrum of MC EVN and have implications in terms of diagnosis, therapy and terminology