Wistar Scientists Discover New Immunosuppressive Mechanism in Brain Cancer
May 03 2024 - 11:32AM
Wistar Scientists Discover New Immunosuppressive Mechanism in Brain
Cancer
The Wistar Institute assistant 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.
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