Rosa Rubicondior: Malevolent Designer News - How Brain Cancer Turns Our Immune System Against Us

The Wistar Institute Discovers a Promising Target in Brain Cancer - The Wistar Institute

It's an old trick often used by creationism's divine malevolence to turn a host's immune system against it and instead work for the parasite.

And, according to a discovery by researchers at the Wistar Institute, this is exactly what one of the most aggressive forms of brain cancer does by reprogramming the white blood cells known as neutrophils, so they supress any further immune response to the cancer.

Of course, whether you accept that or not depends on whether you've fallen for the disinformation promulgated by Deception Institute fellows such as William A Dembski and other leading apologists for the intelligent design cult. Dembski, for example, promotes the notion that genes which produce any given functional protein only do so if they've been given 'complex specified information' to enable them to produce that particular protein.

His presuppositional circular reasoning goes something like, the output from a gene must have been intentional and intent implies sentience, so an intelligent designer must have supplied the information in order to achieve a desired outcome. This of course ignores the fact that mutation and selection occurs in a gene pool consisting of millions of cells and not as a single event in a single cell. In a population of a million cells, the million to one chance mutation arises on average once every cell generation.

A cancer, which is a collection of cells in a hostile environment, can evolve by natural selection to survive and replicate in that environment, so the outcome will depend on the result of an evolutionary arms race.

But, using Dembski's self-referencing logic, believers in intelligent design have to accept that the 'complex specified information' that enables brain tumours to reprogram neutrophils and so supress the immune system, must have been provided by an intelligent designer to achieve exactly that result, because, so he wrongly argues, mutation and natural selection alone can't produce a strategy for survival.

The bad news for supporters of Dembski's divine malevolence is that the discovery by researchers at the Wistar Institute may have tipped the balance in the arms race between human medical science and the malevolent designer in favour of human medical science, in that it suggests a form of treatment for this type of brain cancer.

What information do you have on the role of the protein CD71 in the immune system's response to cancer? CD71, also known as transferrin receptor 1 (TfR1), plays a crucial role in iron homeostasis by mediating cellular iron uptake. It is widely expressed in proliferating cells, including cancer cells and activated immune cells, due to their high iron demand.

Role of CD71 in the Immune System’s Response to Cancer:

Iron Regulation and Immune Function:

CD71 is essential for immune cell proliferation, particularly in T cells and macrophages, as they require iron for metabolic activity.
Iron availability affects immune responses; iron depletion can suppress T cell function, while excess iron can promote oxidative stress and immune suppression.

CD71 as a Marker of Tumour-Associated Immune Cells:

Myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) often express high levels of CD71.
These immune cells contribute to immune evasion by promoting an immunosuppressive tumour microenvironment.

CD71 and Immunosuppressive T Cells:

Regulatory T cells (Tregs) in tumours may exploit CD71-mediated iron metabolism to maintain their suppressive function.
CD71 expression has been linked to metabolic adaptations that support immune evasion in cancer.

CD71 as a Therapeutic Target:

Since many cancer cells overexpress CD71 to support rapid proliferation, it has been explored as a therapeutic target.
Anti-CD71 antibodies and iron deprivation strategies are being investigated to inhibit tumour growth and potentially modulate the immune response.
Some studies suggest that targeting CD71 may enhance the activity of cytotoxic immune cells against tumours.

Role in Ferroptosis and Immune Response:

Ferroptosis (iron-dependent cell death) is a potential mechanism through which CD71 expression affects cancer immunity.
Some therapies aim to induce ferroptosis in cancer cells while preserving immune function.

The discovery of how brain tumours turn our immune system against us is the subject of a Wistar Institute press release and a paper in Cancer Discovery:

The Wistar Institute Discovers a Promising Target in Brain Cancer
Researchers’ Discovery Leads to Effective Anti-Tumor Treatment in Lab
The lab of Filippo Veglia, Ph.D., at The Wistar Institute has discovered a previously unknown mechanism for how aggressive brain cancers reprogram immune system cells from fighting cancer to enabling further tumor growth. The team’s findings were published in the paper “Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation,” from Cancer Discovery.

Brain and nervous system tumors are some of cancer’s most lethal forms; someone diagnosed with this type of cancer has a roughly one in three chance of surviving the next five years. Certain immunotherapies that stimulate the immune system to target specific cancer markers have shown progress against several brain cancers, but in many cases (and even more frequently in the most severe forms of brain cancer, like glioblastoma), the presence of tumor-infiltrating neutrophils is the key factor that has prevented these therapies from working.

Neutrophils are a type of white blood cell that the immune system uses to attack cancer in its early stages. However, scientists have discovered that, if a tumor survives the body’s initial defenses and continues to grow, these tumor-associated neutrophils actually start to work for the tumor rather than against it by suppressing further anti-cancer interventions from the immune system.

Now, scientists know how glioblastoma reprograms tumor-infiltrating neutrophils. In their new paper, Wistar’s Dr. Filippo Veglia and his team set out to understand the mechanisms behind brain cancer’s reprogramming of neutrophils — and how to stop it.

Researchers investigated the subset of neutrophils found almost exclusively within the brain tumor in preclinical models of brain cancer. Analysis showed that 25-30% of these tumor-infiltrating neutrophils expressed the CD71 protein, which was notably absent from most of the other neutrophils outside the brain tumor.

The team tested the immunosuppressive activity of intra-tumor CD71 positive (CD71+) neutrophils and found that they reduced immune system activity where CD71 negative (CD71–) neutrophils did not. These immunosuppressive effects, the team found, were heightened in hypoxic (oxygen-deprived) environments like the hypoxic regions within the tumor where CD71+ neutrophils occur. Further analysis revealed that hypoxic CD71+ neutrophils expressed an additional gene, ARG1, that caused the immunosuppressive effect. Without ARG1, even hypoxic CD71+ neutrophils did not suppress the immune system, according to the researchers’ analysis.

The hypoxic CD71+ neutrophils had come to acquire ARG1 expression and its immunosuppressive effects, but researchers did not yet know how. Dr. Veglia and team suspected an interplay between hypoxia and neutrophils’ glucose metabolism was the root cause; the original suspect group of neutrophils from within the brain tumor (hypoxic CD71+ neutrophils) had shown increased indicators of glucose metabolism and lactate accumulation.

By inhibiting both glucose metabolism and the hypoxic CD71+ neutrophils’ ability to process lactate, researchers eliminated the neutrophils’ ability to suppress immune responses, which proved that both glucose metabolism and lactate accumulation were critical to the immunosuppressive reprogramming.

At this point, researchers knew that hypoxic CD71+ neutrophils, through glucose metabolism and lactate accumulation, acquired ARG1 expression, which would cause the neutrophils to suppress the immune system.

One crucial question remained: why would glucose metabolism and lactate accumulation cause ARG1 to be expressed?

The research team drew from an influential study that showed how gene expression could be changed through a process called histone lactylation. Histones are proteins that govern the structure of our genes, and certain changes to histones can cause genes to be turned on or off. In histone lactylation, incompletely metabolized lactate produces by-products that attach molecules called lactyl groups to histones, and those modified histones cause changes in gene expression.

When researchers looked for signs of this histone lactylation in hypoxic CD71+ neutrophils, they confirmed their suspicions. Not only did the CD71+ neutrophils show higher levels of histone lactylation markers than CD71– neutrophils — the histone lactylation markers were high in the region of the ARG1 gene, an indication that the histone lactylation process had caused the ARG1 gene to be turned on. By selectively turning off the neutrophils’ ability to carry out histone lactylation, the researchers successfully reduced ARG1 expression.

Dr. Veglia and team discovered the central process causing neutrophil reprogramming: neutrophils infiltrate the brain tumor; hypoxic tumor regions recruit neutrophils, including those expressing CD71; the hypoxic CD71+ neutrophils increase their glucose metabolism, which causes lactate production to increase; the excess lactate causes histone lactylation; the histone lactylation causes ARG1 expression; and the ARG1 expression suppresses the activity and signaling of other immune cells.

Using their knowledge of the neutrophil reprogramming process, the team developed a therapeutic approach to stop the pro-cancer effect. They used the anti-epileptic compound isosafrole, which inhibited a key lactate-processing enzyme. In preclinical laboratory testing, isosafrole treatment reduced histone lactylation, resulting in an impaired ARG1 expression and immunosuppression of hypoxic CD71+ neutrophils, without negatively affecting other immune cells. By combining isosafrole treatment with a targeted brain cancer immunotherapy — which has previously struggled to succeed due to the cancer’s immunosuppression — Dr. Veglia and team overcame the resistance to immunotherapy and substantially slowed tumor progression in preclinical models.

Our work shows the step-by-step process of how brain tumors can cause an immune system’s neutrophils to become deadly barriers to cancer treatment. Now that we understand this reprogramming process, we know how to interrupt it, and already, preclinical data show that isosafrole treatment that disrupts neutrophil reprogramming can make poor-prognosis brain tumors responsive to immunotherapy. We look forward to seeing how future research can refine this strategy to fight some of the deadliest cancers.

Dr. Philippo Veglia, lead author
The Wistar Institute
Philadelphia, United States.

Abstract

Despite functional heterogeneity, high frequency of intratumoral neutrophils predicts poor clinical outcomes. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anti-cancer immunity, thereby contributing to tumor growth and resistance to immunotherapies. However, the mechanisms underlying neutrophil reprogramming remain elusive. Here, we report that the immunosuppressive ability of brain tumor-infiltrating neutrophils was restricted to a highly glycolytic and long-lived subset expressing CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+neutrophils, leading to high lactate production. Lactate caused histone lactylation, which subsequently regulated arginase-1 expression, required for T cell suppression. Targeting histone lactylation with the anti-epileptic drug isosafrole blocked CD71+neutrophil immunosuppressive ability, delayed tumor progression and sensitized brain tumors to immunotherapy. A distinctive gene signature characterizing immunosuppressive CD71+neutrophils correlated with adverse clinical outcomes across diverse human malignancies. This study identifies histone lactylation as a potential therapeutic target to counteract neutrophil-induced immunosuppression within tumors.

Alessio Ugolini, Alessandra De Leo, Xiaoqing Yu, Fabio Scirocchi, Xiaoxian Liu, Barbara Peixoto, Delia Scocozza, Angelica Pace, Michela Perego, Alessandro Gardini, Luca D'Angelo, James K C. Liu, Arnold B. Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A. Vogelbaum, Jose R. Conejo-Garcia, Paulo C. Rodriguez, Filippo Veglia;
Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation. Cancer Discov 2025; https://doi.org/10.1158/2159-8290.CD-24-1056

© 2025 the American Association for Cancer Research.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

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