Tumor-associated neutrophils are highly abundant in primary and metastatic brain tumors, have an immunosuppressive and pro-angiogenic phenotype, and are altered by secreted factors produced by a network of tumor-associated myeloid cells.
The research*, published in Cell, was conducted by Roeltje Maas and colleagues and directed by Prof. Johanna Joyce, member of the Lausanne Branch of the Ludwig Institute for Cancer Research.
Brain tumors encompass a variety of cancers, broadly categorized as primary or metastatic. Primary brain tumors, such as low- and high-grade gliomas, exhibit significant differences in patient prognosis. Brain metastases (BrM) are estimated to manifest in over 20% of cancer patients, particularly those with primary lung cancer, breast cancer, or melanomas. Contemporary cancer therapies increasingly emphasize immunotherapies, although their effectiveness is limited to a subset of BrM patients and shows minimal responses in glioma patients. The suboptimal efficacy of immunotherapy in brain cancers is believed to be influenced by the immunosuppressive features of the brain tumor microenvironment (TME).
This research revealed a substantial accumulation of tumor-associated neutrophils (TANs) in high-grade gliomas and BrMs, exhibiting a pro-tumoral phenotype characterized by immunosuppression, pro-angiogenic capabilities, and prolonged survival. Notably, the authors identified tumor type-specific inflammatory alterations, prominently found in BrMs. The induction of the immunosuppressive TAN phenotype was chiefly orchestrated by TNF-a and Ceruloplasmin, predominantly produced by myeloid cells within the brain TME. These findings offer potential novel avenues for treatment by modifying the immunosuppressive nature of the brain TME to enhance the efficacy of immunotherapies.
Lastly, all the transcriptomic data generated in this study is openly accessible to the research community. The Joyce lab has integrated this valuable data with their previously published studies into an interactive open-access platform, enhancing its accessibility and usability as a unique and comprehensive resource: Brain TIME – Brain Tumor Immune Microenvironment Platform (see link on the right).
The research was supported by the Swiss National Science Foundation Advanced Grant TMAG-3_209224, the University of Lausanne (UNIL), the Ludwig Institute for Cancer Research, ISREC Foundation, Breast Cancer Research Foundation, Carigest Foundation, Swiss Bridge Award, and the Department of Oncology (CHUV).
*The local microenvironment drives activation of neutrophils in human brain tumors