Discovery of a novel immunosuppressive pathway in brain cancer

Dr. Filippo Veglia and his team at the Wistar Institute have made an important discovery in understanding how glioblastoma, a deadly brain cancer, suppresses the immune system to facilitate its unhindered growth. In their research, they found that monocyte-derived macrophages play a key role in creating an immunosuppressive environment in glioblastomas, preventing the body’s immune system from attacking the cancer cells. By studying the cellular mechanisms of cancer self-preservation, the team hopes to find new ways to fight this aggressive cancer.

Glioblastoma is a highly malignant brain cancer with a poor prognosis, and current treatment options are limited. The tumor’s ability to suppress the immune system makes it resistant to immunotherapies, further complicating treatment efforts. By identifying the role of monocyte-derived macrophages in promoting an immunosuppressive tumor microenvironment, the Veglia lab aims to develop strategies to target these cancer-related immune cells and restore the body’s ability to fight the cancer.

Through gene expression and metabolic analysis, the research team found that monocyte-derived macrophages with enhanced glucose metabolism play a critical role in promoting immunosuppression in glioblastoma. These macrophages release interleukin-10, an important immunosuppressive factor, which blocks the activity of T cells that normally attack tumor cells. By targeting the glucose metabolism of these macrophages, the team hopes to disrupt the immunosuppressive environment and increase the effectiveness of immune responses against cancer.

One of the major mechanisms by which monocyte-derived macrophages promote immunosuppression is lactylation of histones, which influences gene expression patterns that support tumor growth. By understanding this process, the researchers identified a potential target for intervention: an enzyme called PERK that regulates glucose metabolism and histone lactylation in macrophages. In preclinical models, targeting PERK was shown to impair histone lactylation and immunosuppressive activity of macrophages, resulting in improved outcomes and long-lasting immunity against glioblastoma.

The team’s findings provide new insights into the cellular mechanisms driving immunosuppression in glioblastoma and provide a potential strategy for developing more effective treatments for this deadly cancer. By targeting the PERK-histone lactylation axis, researchers may be able to disrupt the immunosuppressive environment created by monocyte-derived macrophages and increase the body’s ability to mount an immune response against the cancer. This research represents an important step forward in the understanding and treatment of glioblastoma and offers hope for better outcomes for patients with this aggressive form of brain cancer.