Effective Reprogramming of Patient-Derived M2-Polarized Glioblastoma-Associated Microglia/Macrophages by Treatment with GW2580.

PURPOSE: Targeting immunosuppressive and pro-tumorigenic glioblastoma (GBM)-associated macrophages and microglial cells (GAM) has great potential to improve patient outcomes. Colony-stimulating factor-1 receptor (CSF1R) has emerged as a promising target for reprograming anti-inflammatory M2-like GAMs. However, treatment data on patient-derived, tumor-educated GAMs and their influence on the adaptive immunity are lacking. EXPERIMENTAL DESIGN: CD11b+-GAMs freshly isolated from patient tumors were treated with CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. Phenotypical changes upon treatment were assessed using RNA sequencing, flow cytometry, and cytokine quantification. Functional analyses included inducible nitric oxide synthase activity, phagocytosis, transmigration, and autologous tumor cell killing assays. Antitumor effects and changes in GAM activation were confirmed in a complex patient-derived 3D tumor organoid model serving as a tumor avatar. RESULTS: The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to the downregulation of M2-related markers, IL6, IL10, ERK1/2, and MAPK signaling pathways, while M1-like markers, gene set enrichment indicating activated MHC-II presentation, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived GBM organoids with GW2580 confirmed successful reprogramming, resulting in impaired tumor cell proliferation. In line with its failure in clinical trials, PLX3397 was ineffective in our analysis. CONCLUSIONS: This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human GBM avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T-cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for GBM.

Luminescent Pyrrole-Based Phosphaphenalene Gold Complexes: Versatile Anticancer Tools with Wide Applicability.

Invited for the cover of this issue are the groups of Christel Herold-Mende and Carlos Romero-Nieto at the Universities of Heidelberg and Castilla-La Mancha. The image depicts the use of phosphaphenalene gold(I) complexes for the treatment of brain cancer. Read the full text of the article at 10.1002/chem.202104535.

Luminescent Pyrrole-Based Phosphaphenalene Gold Complexes: Versatile Anticancer Tools with Wide Applicability.

Brain cancer, one of the most lethal diseases, urgently requires the discovery of novel theranostic agents. In this context, molecules based on six-membered phosphorus heterocycles - phosphaphenalenes - are especially attractive; they possess unique characteristics that allow precise chemical engineering. Herein, we demonstrate that subtle structural modifications of the phosphaphenalene-based gold(I) complexes lead to modify their electronic distribution, endow them with marked photophysical properties and enhance their efficacy against cancer. In particular, phosphaphenalene-based gold(I) complexes containing a pyrrole ring show antiproliferative properties in 14 cell lines including glioblastomas, brain metastases, meningiomas, IDH-mutant gliomas and head and neck cancers, reaching IC50 values as low as 0.73 µM. The bioactivity of this new family of drugs in combination with their photophysical properties thus offer new research possibilities for both the fundamental investigation and treatment of brain cancer.

Correction: Gold(I) complexes based on six-membered phosphorus heterocycles as bio-active molecules against brain cancer.

Correction for 'Gold(i) complexes based on six-membered phosphorus heterocycles as bio-active molecules against brain cancer' by Saskia Roesch et al., Chem. Commun., 2020, DOI: 10.1039/d0cc05761d.

Gold(i) complexes based on six-membered phosphorus heterocycles as bio-active molecules against brain cancer.

π-Systems based on six-membered phosphorus heterocycles possess structural and electronic characteristics that clearly distinguish them from the rest of the organophosphorus molecules. However, their use in cancer therapy has been uninvestigated. In particular, glioblastoma is one of the most lethal brain tumors. The development of novel and more efficient drugs for the treatment of glioblastoma is thus crucial to battle this aggressive disease. Herein, we report a new family of gold(i) complexes based on six-membered phosphorus heterocycles as a promising tool to investigate brain cancer. We discovered that the latter complexes inhibit the proliferation, sensitize to apoptosis and hamper the migration of not only conventional but also stem-like glioblastoma cells. Our results unveil thus new research opportunities for the treatment of glioblastoma.

Single-nucleus chromatin accessibility reveals intratumoral epigenetic heterogeneity in IDH1 mutant gliomas.

The presence of genome-wide DNA hypermethylation is a hallmark of lower grade gliomas (LGG) with isocitrate dehydrogenase (IDH) mutations. Further molecular classification of IDH mutant gliomas is defined by the presence (IDHmut-codel) or absence (IDHmut-noncodel) of hemizygous codeletion of chromosome arms 1p and 19q. Despite the DNA hypermethylation seen in bulk tumors, intra-tumoral heterogeneity at the epigenetic level has not been thoroughly analyzed. To address this question, we performed the first epigenetic profiling of single cells in a cohort of 5 gliomas with IDH1 mutation using single nucleus Assay for Transposase-Accessible Chromatin with high-throughput sequencing (snATAC-seq). Using the Fluidigm HT IFC microfluidics platform, we generated chromatin accessibility maps from 336 individual nuclei, and identified variable promoter accessibility of non-coding RNAs in LGGs. Interestingly, local chromatin structures of several non-coding RNAs are significant factors that contribute to heterogeneity, and show increased promoter accessibility in IDHmut-noncodel samples. As an example for clinical significance of this result, we identify CYTOR as a poor prognosis factor in gliomas with IDH mutation. Open chromatin assay points to differential accessibility of non-coding RNAs as an important source of epigenetic heterogeneity within individual tumors and between molecular subgroups. Rare populations of nuclei that resemble either IDH mutant molecular group co-exist within IDHmut-noncodel and IDHmut-codel groups, and along with non-coding RNAs may be an important issue to consider for future studies, as they may help guide predict treatment response and relapse.A web-based explorer for the data is available at shiny.turcanlab.org.

Identification of T cell target antigens in glioblastoma stem-like cells using an integrated proteomics-based approach in patient specimens.

Glioblastoma (GBM) is a highly aggressive brain tumor and still remains incurable. Among others, an immature subpopulation of self-renewing and therapy-resistant tumor cells-often referred to as glioblastoma stem-like cells (GSCs)-has been shown to contribute to disease recurrence. To target these cells personalized immunotherapy has gained a lot of interest, e.g. by reactivating pre-existing anti-tumor immune responses against GSC antigens. To identify T cell targets commonly presented by GSCs and their differentiated counterpart, we used a proteomics-based separation of GSC proteins in combination with a T cell activation assay. Altogether, 713 proteins were identified by LC-ESI-MS/MS mass spectrometry. After a thorough filtering process, 32 proteins were chosen for further analyses. Immunogenicity of corresponding peptides was tested ex vivo. A considerable number of these antigens induced T cell responses in GBM patients but not in healthy donors. Moreover, most of them were overexpressed in primary GBM and also highly expressed in recurrent GBM tissues. Interestingly, expression of the most frequent T cell target antigens could also be confirmed in quiescent, slow-cycling GSCs isolated in high purity by the DEPArray technology. Finally, for a subset of these T cell target antigens, an association between expression levels and higher T cell infiltration as well as an increased expression of positive immune modulators was observed. In summary, we identified novel immunogenic proteins, which frequently induce tumor-specific T cell responses in GBM patients and were also detected in vitro in therapy-resistant quiescent, slow-cycling GSCs. Stable expression of these T cell targets in primary and recurrent GBM support their suitability for future clinical use.

Congenital prosopagnosia is associated with a genetic variation in the oxytocin receptor (OXTR) gene: An exploratory study.

Face-recognition deficits, referred to with the term prosopagnosia (i.e., face blindness), may manifest during development in the absence of any brain injury (from here the term congenital prosopagnosia, CP). It has been estimated that approximately 2.5% of the population is affected by face-processing deficits not depending on brain lesions, and varying a lot in severity. The genetic bases of this disorder are not known. In this study we tested for genetic association between single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) and CP in a restricted cohort of Italian participants. We found evidence of an association between the common genetic variants rs53576 and rs2254298 OXTR SNPs and prosopagnosia. This association was also found when including an additional group of German individuals classified as prosopagnosic in the analysis. Our preliminary data provide initial support for the involvement of genetic variants of OXTR in a relevant cognitive impairment, whose genetic bases are still largely unexplored.