Researchers at The Wistar Institute, led by assistant professor Filippo Veglia, Ph.D., have identified a crucial way in which glioblastoma, a deadly form of brain cancer, is able to avoid detection by the immune system. Their findings, published in the journal Immunity, reveal that the cancer uses a glucose-based epigenetic modification to induce pro-tumor macrophages, suppressing the body’s natural defenses and allowing the tumor to thrive.
Dr. Veglia stated that our research demonstrates that understanding the cellular processes that allow cancer to protect itself can be a powerful tool in fighting the disease. He expressed optimism for future studies on the immunosuppressive mechanisms driven by metabolism in glioblastoma, and the potential for further advancements in the understanding and treatment of this cancer.
Until now, there has been limited understanding of how monocyte-derived macrophages and microglia contribute to the creation of an immunosuppressive environment in glioblastoma. The Veglia lab explored the specific cellular processes involved in this phenomenon.Unosuppression research has found that as glioblastoma progresses, monocyte-derived macrophages outnumber microglia, suggesting that the eventual dominance of monocyte-derived macrophages in the tumor microenvironment benefits the cancer’s ability to evade immune response. In both preclinical models and patients, it was also discovered that monocyte-derived macrophages, but not microglia, inhibit the activity of T cells, which are immune cells that fight tumor cells. This finding was further confirmed when preclinical models of glioblastoma were artificially manipulated to reduce the number of monocyte-derived macrophages. The researchers anticipate that these findings will have significant implications.The study found that glioblastoma models with fewer harmful immune cells in the tumor microenvironment had better outcomes compared to standard models. Glioblastoma makes up more than half of all brain cancers and has a poor prognosis, with only 25% of patients surviving for more than a year after diagnosis. Its location in the brain and its ability to suppress the immune system make it resistant to immunotherapies. By modifying immune cells like macrophages, researchers hope to improve treatment outcomes for glioblastoma.(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.
After confirming the role of monocyte-derived macrophages, the Veglia lab then wanted to understand how the cancer-supporting immune cells were working against the immune system. They analyzed the genetic sequencing of the macrophages to see if there were any abnormal gene expression patterns that could indicate which gene(s) might be involved in immunosuppression. The researchers analyzed the metabolic patterns of macrophages to investigate whether the unique gene expression of the macrophages could be linked to their metabolism. The team’s combined analysis of gene expression and metabolism pointed to glucose metabolism as a key factor. After conducting a series of tests, the Veglia lab discovered that monocyte-derived macrophages with increased glucose metabolism and the expression of GLUT1, a major glucose transporter, inhibited the function of T cells by releasing interleukin-10 (IL-10). The team demonstrated that the altered glucose metabolism in these macrophages, caused by glioblastoma, led to their immunosuppressive activity.The team found that the ability of macrophages to suppress the immune system through glucose metabolism hinges on a process known as “histone lactylation.” Histones are proteins in the genome that play a role in determining which genes, such as IL-10, are expressed in specific circumstances. Monocyte-derived macrophages, which rapidly metabolize glucose, produce lactate as a by-product. This lactate can become incorporated into histones in a process called “lactylation,” promoting the expression of IL-10.
In a study conducted by Dr. Veglia and his research team, they found that monocyte-derived macrophages play a role in promoting the growth of cancer cells through their glucose-driven immunosuppressive activity. To address this issue, the researchers looked into the potential of targeting an enzyme called PERK, which is known to regulate glucose metabolism and the expression of GLUT1 in macrophages. Their findings showed that by targeting PERK in preclinical models of glioblastoma, they were able to reduce the immunosuppressive activity of macrophages and block the progression of glioblastoma when combined with immunotherapy. This approach also led to the development of long-lasting immunity against tumor re-growth in the brain, demonstrating the potential of targeting PERK as a treatment strategy for cancer.
The use of lactylation axis may be an effective approach to combat the deadly brain cancer. It is worth noting that the research described in this publication was started at The H. Lee Moffitt Cancer Center during Dr. Veglia’s tenure and then continued at Wistar.
