GlobeNewswire by notified

Wistar Scientists Discover New Immunosuppressive Mechanism in Brain Cancer


Wistar’s Veglia lab identified how glioblastoma evades the immune system by inducing pro-tumor macrophages via a glucose based epigenetic modification.

PHILADELPHIA, PA, May 03, 2024 (GLOBE NEWSWIRE) -- The Wistar Instituteassistant professor Filippo Veglia, Ph.D., and team, have discovered a key mechanism of how glioblastoma — a serious and often fatal brain cancer — suppresses the immune system so that the tumor can grow unimpeded by the body’s defenses. The lab’s discovery was published in the paper, “Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma,” in the journal Immunity.

“Our study shows that the cellular mechanisms of cancer’s self-preservation, when sufficiently understood, can be used against the disease very effectively,” said Dr. Veglia. “I look forward to future research on metabolism-driven mechanisms of immunosuppression in glioblastoma, and I’m hopeful for all that we will continue to learn about how to best understand and fight this cancer.”

Until now, it has been poorly understood how monocyte-derived macrophages and microglia create an immunosuppressive tumor microenvironment in glioblastoma. The Veglia lab investigated the cellular “how” of glioblastoma immunosuppression and identified that, as glioblastoma progressed, monocyte-derived macrophages came to outnumber microglia — which indicated that monocyte-derived macrophages’ eventuality to becoming the majority in the tumor microenvironment was advantageous to the cancer’s goal of evading immune response. Indeed, monocyte-derived macrophages, but not microglia, blocked the activity of T cells (immune cells that destroy tumor cells), in preclinical models and patients. The team confirmed this finding when they assessed preclinical models of glioblastoma with artificially reduced numbers of monocyte-derived macrophages. And as the group expected, the models with fewer malicious macrophages in the tumor microenvironment showed improved outcomes relative to the standard glioblastoma models. 

Glioblastoma accounts for slightly more than half of all malignancies that originate in the brain, and the prognosis for those diagnosed with the cancer is quite poor: only 25% of patients who receive a glioblastoma diagnosis will survive beyond a year. Glioblastoma is inherently dangerous due to its location in the brain and its immunosuppressive tumor microenvironment, which renders glioblastoma resistant to promising immunotherapies. By programming certain immune cells like macrophages, (such as monocyte-derived macrophages and microglia), to work for — rather than against — the tumor, glioblastoma fosters a tumor microenvironment for itself that enables the cancer to grow aggressively while evading anticancer immune responses.

Having confirmed the role of monocyte-derived macrophages, the Veglia lab then sought to understand just how the cancer-allied immune cells were working against the immune system. They sequenced the macrophages in question to see whether the cells had any aberrant gene expression patterns that could point to which gene(s) could be playing a role in immunosuppression, and they also investigated the metabolic patterns of macrophages to see whether the macrophages’ nonstandard gene expression could be tied to metabolism. 

The team’s twin gene expression & metabolic analysis led them to glucose metabolism. Through a series of tests, the Veglia lab was able to determine that monocyte-derived macrophages with enhanced glucose metabolism and expressing GLUT1, a major transporter for glucose (a key metabolic compound), blocked T cells’ function by releasing interleukin-10 (IL-10). The team demonstrated that glioblastoma-perturbed glucose metabolism in these macrophages induced their immunosuppressive activity.

The team discovered the key to macrophages’ glucose-metabolism-driven immunosuppressive potency lies in a process called “histone lactylation.” Histones are structural proteins in the genome that play a key role in which genes — like IL-10 — are expressed in which contexts. As rapidly glucose-metabolizing cells, monocyte-derived macrophages produce lactate, a by-product of glucose metabolism. And histones can become “lactylated” (which is when lactate becomes incorporated into histones) in such a way that the histones’ organization further promotes the expression of IL-10 — which is effectively produced by monocyte-derived macrophages to help cancer cells to grow.

But how can the glucose-driven immunosuppressive activity of monocyte-derived macrophages be stopped? Dr. Veglia and his research team identified a possible solution: PERK, an enzyme they had identified as regulating glucose metabolism and GLUT1 expression in macrophages. In preclinical models of glioblastoma, targeting PERK impaired histone lactylation and immunosuppressive activity of macrophages, and in combination with immunotherapy blocked glioblastoma progression and induced long-lasting immunity that protected the brain from tumor re-growth — a sign that targeting PERK-histone lactylation axis may be a viable strategy for fighting this deadly brain cancer. 

Note: The work detailed in this publication was initiated at The H. Lee Moffitt Cancer Center during Dr. Veglia’s time there and continued at Wistar.

Co-authors: Alessandra De Leo, Alessio Ugolini, Fabio Scirocchi, Delia Scocozza, Barbara Peixoto, Paulo C. Rodriguez, and Filippo Veglia of the Department of Immunology at the H. Lee Moffitt Cancer Center; James K. C. Liu, Arnold B. Etame, Michael A. Vogelbaum, and Filippo Veglia of the Department of Neuro-Oncology at the H. Lee Moffitt Cancer Center; Xiaoqing Yu of the Department of Biostatistics and Bioinformatics at the H. Lee Moffitt Cancer Center; Alessandra De Leo, Alessio Ugolini, Barbara Peixoto and Filippo Veglia of The Wistar Institute; Alessio Ugolini, Fabio Scirocchi, Angelica Pace, Aurelia Rughetti and Marianna Nuti of the Department of Experimental Medicine at Sapienza University of Rome; Luca D’Angelo and Antonio Santoro of the Department of Human Neurosciences at Sapienza University of Rome; and Jose R. Conejo-Garcia of Duke School of Medicine.

Work supported by: This work was supported by The Ben & Catherine Ivy Foundation Emerging Adult Glioma Award, The National Institute of Neurological Disorders and Stroke (1R01NS131912-01), by American Cancer Society Institutional Research Grant (IRG-21-145-25). It is supported in part by the Flow Cytometry Core Facility, the Molecular Genomics Core, Proteomics & Metabolomics Core Facility, Biostatistics and Bioinformatics Shared Resource at the H. Lee Moffitt Cancer Center & Research Institute, a Comprehensive Cancer Center designated by the National Cancer Institute and funded in part by Support Grant (P30-CA076292). Human specimen collection (Policlinico Umberto I) was in part supported by grant RM120172B803DB14.

Publication information:Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma,” from Immunity.

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers.

To view this piece of content from, please give your consent at the top of this page.
To view this piece of content from, please give your consent at the top of this page.

About GlobeNewswire by notified

GlobeNewswire by notified
GlobeNewswire by notified
One Liberty Plaza - 165 Broadway
NY 10006 New York

GlobeNewswire by notified is one of the world's largest newswire distribution networks, specializing in the delivery of corporate press releases financial disclosures and multimedia content to the media, investment community, individual investors and the general public.

Subscribe to releases from GlobeNewswire by notified

Subscribe to all the latest releases from GlobeNewswire by notified by registering your e-mail address below. You can unsubscribe at any time.

Latest releases from GlobeNewswire by notified

Subsea7 awarded a contract for the Belinda field in the UK North Sea25.5.2024 14:01:09 CEST | Press release

Luxembourg – 25 May 2024 - Subsea7 S.A. (Oslo Børs: SUBC, ADR: SUBCY) today announced the award of a sizeable1 contract by Serica Energy, for the Belinda field development south-east of the Triton FPSO. The Belinda field is operated by Serica Energy and located approximately 190 kilometres east of Aberdeen in the UK Central North Sea, with a water depth of 95 metres. The contract scope includes project management, engineering, procurement, construction and installation (EPCI) of a 5-kilometre 8” production pipeline with a 3” piggy-backed gas lift line and an electro-hydraulic controls (EHC) umbilical. Subsea7’s scope also includes associated subsea structures and tie-ins to the Triton Floating Production Storage & Offloading (FPSO) vessel operated by Dana Petroleum, via an existing production manifold near the Triton riser base and for controls at the Evelyn valve skid. Project management and engineering work will commence immediately in Aberdeen. The offshore activities are scheduled

Novartis atrasentan Phase III data show clinically meaningful proteinuria reduction further advancing company's IgA nephropathy (IgAN) portfolio25.5.2024 12:15:00 CEST | Press release

In the ALIGN study, atrasentan, in addition to supportive care with a renin-angiotensin system (RAS) inhibitor,demonstrated a statistically significant 36.1% proteinuria (protein in urine) reduction vs. placebo + supportive care at 36 weeks1 Endothelin A (ETA) receptor activation contributes to elevated proteinuria in IgAN2-5; atrasentan is a potent, selective ETA receptor antagonist with potential to reduce persistent proteinuria and preserve kidney function for a broad patient population1 IgAN is a heterogeneous, progressive, rare kidney disease with a need for effective, targeted therapies6,7; up to 30% of patients with persistent proteinuria (≥1 g/day) progress to kidney failure within 10 years8 Through its rare kidney disease portfolio, Novartis is committed to exploring a range of treatment options with different modes of action to slow IgAN progression Basel, May 25, 2024 – Novartis today presented results from a pre-specified interim analysis of the Phase III ALIGN study of atr

Novartis presents latest Phase III Fabhalta® (iptacopan) data in C3 glomerulopathy (C3G) showing clinically meaningful and statistically significant 35.1% proteinuria reduction vs. placebo25.5.2024 12:00:00 CEST | Press release

Secondary endpoint data for estimated glomerular filtration rate (eGFR) showed numerical improvement over 6 months vs. placebo1; additional 6-month open-label data to be presented at a future medical meeting2,3Fabhalta showed a favorable safety profile with no new safety signals1C3G, an ultra-rare kidney disease caused by alternative complement pathway overactivation, progresses to kidney failure in ∼50% of patients within 10 years4-7; currently there are no treatments approved for C3G7-9 Fabhalta, an oral Factor B inhibitor of the alternative complement pathway, selectively targets the underlying cause of C3G1; late-stage development program ongoing across several other rare diseases10-13 Basel, May 25, 2024 – Novartis today presented results from the 6-month, double-blind period of the Phase III APPEAR-C3G study of Fabhalta® (iptacopan) at the late-breaking clinical trials session of the European Renal Association (ERA) Congress1. Patients treated with Fabhalta in addition to support

Metasphere Labs Announces Development of Innovative Carbon Credit Protocol for Grid-Scale Batteries24.5.2024 22:05:00 CEST | Press release

VANCOUVER, British Columbia, May 24, 2024 (GLOBE NEWSWIRE) -- Metasphere Labs Inc. (formerly Looking Glass Labs Ltd., "Metasphere" or the "Company") (Cboe Canada: LABZ) (OTC: LABZF) (FRA: H1N) is excited to announce an innovative initiative aimed at accelerating the decarbonization of the electricity grid through the development of a pioneering carbon credit protocol for grid-scale batteries. Innovative Carbon Credit Protocol The Company is committed to leveraging advanced technology to address critical environmental challenges. The new carbon credit protocol will enable grid-scale batteries to monetize their environmental attributes by generating carbon credits for the carbon reductions achieved through optimized battery operations. This protocol is designed to incentivize the deployment and operation of grid-scale batteries, ensuring they play a pivotal role in the transition to a clean energy future. Submission to Pure Sky Carbon Credit Registry The Company intends to submit this pr

Nokia Corporation: Repurchase of own shares on 24.05.202424.5.2024 21:30:00 CEST | Press release

Nokia Corporation Stock Exchange Release 24 May 2024 at 22:30 EEST Nokia Corporation: Repurchase of own shares on 24.05.2024 Espoo, Finland – On 24 May 2024 Nokia Corporation (LEI: 549300A0JPRWG1KI7U06) has acquired its own shares (ISIN FI0009000681) as follows: Trading venue (MIC Code)Number of sharesWeighted average price / share, EUR*XHEL362,1533.55CEUX--BATE--AQEU--TQEX--Total362,1533.55 * Rounded to two decimals On 25 January 2024, Nokia announced that its Board of Directors is initiating a share buyback program to return up to EUR 600 million of cash to shareholders in tranches over a period of two years. The first phase of the share buyback program in compliance with the Market Abuse Regulation (EU) 596/2014 (MAR), the Commission Delegated Regulation (EU) 2016/1052 and under the authorization granted by Nokia’s Annual General Meeting on 4 April 2023 started on 20 March 2024 and ends by 18 December 2024 with a maximum aggregate purchase price of EUR 300 million. Total cost of tra

HiddenA line styled icon from Orion Icon Library.Eye