Glioblastoma Induces the Recruitment and Differentiation of Dendritic-like 'Hybrid' Neutrophils from Skull Bone Marrow

Neurology Life Sciences Immunology Oncology Medicine Cell Biology
Glioblastoma Dendritic Cells Neutrophils Skull Bone Marrow Immunotherapy

Glioblastoma Induces Recruitment and Differentiation of Dendritic “Hybrid” Neutrophils via Skull Bone Marrow

Background

Glioblastoma (GBM) is a highly aggressive central nervous system malignancy with very poor prognosis, typically associated with short patient survival. Although significant advancements have been made in tumor treatment technologies and strategies in recent years, traditional radiotherapy and chemotherapy still struggle to achieve satisfactory efficacy. This is because these treatments mainly target the tumor cells themselves and do not adequately consider the supportive role of the tumor microenvironment (TME) in tumor growth and invasiveness. GBM cells attract different types of immune cells by secreting cytokines, chemokines, and growth factors, which influence the tumor’s invasiveness and treatment resistance. While most research has focused on the role of tumor-associated macrophages (TAMs) in GBM, the functions of tumor-associated neutrophils (TANs) in GBM have not been thoroughly studied.

This paper is authored by Meeki Lad and colleagues from the Department of Neurosurgery at the University of California, San Francisco (UCSF) and published in the September 2024 issue of Cancer Cell. The authors for the first time revealed that immature neutrophils from skull bone marrow are induced to polarize into dendritic “hybrid” neutrophils within the GBM microenvironment. This discovery suggests that GBM recruits and induces these neutrophils to polarize in a dendritic cell-like manner, forming immune cells with antigen-presenting functions, thereby activating T cell anti-tumor responses. This study not only provides new insights into the immune microenvironment of GBM but also hints at the potential of targeting skull bone marrow as a therapeutic target for central nervous system (CNS) tumors.

Research Methods

Research Design and Process

The study utilized a combination of in vitro experiments, animal models, and single-cell RNA sequencing (scRNA-seq) technology, and was primarily conducted in the following steps:

  1. Isolation and Analysis of Neutrophils: Tumor-associated neutrophils (TANs) were isolated from GBM patient tumor tissues and compared with peripheral blood neutrophils (PBNs) from the patients in terms of their transcriptomes to analyze differences in genes related to antigen presentation.
  2. Verification of Skull Bone Marrow Origin: Through transplantation experiments, researchers confirmed the migration of immature antigen-presenting cells (APCs) from skull bone marrow to GBM. Transplantation experiments with fluorescently labeled skull bone fragments revealed the unique contribution of skull bone marrow to tumor antigen-presenting cells.
  3. Functional Study of “Hybrid” Neutrophils: Flow cytometry was used to detect the expression of major histocompatibility complex class II molecules (MHCII) on TANs, and both in vivo and in vitro experiments confirmed their role in activating T cells.
  4. Validation of Tumor Suppression Effects: Using a mouse GBM model, the effects on tumor burden and the tumor microenvironment were assessed by depleting TANs or T cells.

Data Analysis and Innovative Technologies

To further explore the functional polarization state of TANs, the authors employed single-cell RNA sequencing (scRNA-seq) to analyze the expression characteristics of genes associated with the antigen presentation pathway, chemotaxis, and phagocytosis in patients’ TANs and PBNs. Additionally, to verify the anti-tumor function of TANs, researchers conducted systematic neutrophil depletion experiments and experiments using the AMD3100 drug to induce migration of skull bone marrow neutrophils, with results supporting the anti-tumor effect of TANs. This pathway of differentiation to acquire antigen-presenting function from bone marrow precursor cells offers a new perspective on understanding the immune microenvironment of GBM.

Research Results

Key Findings

  1. TANs Have Antigen-Presenting Functions: Researchers discovered through flow cytometry and antigen processing tests that the “hybrid” cells in GBM patients’ TANs possess complex morphology, express antigen-presenting genes, and can activate T cells. These “hybrid” neutrophils survive long-term in the GBM microenvironment, challenging the traditional view of neutrophils as short-lived bystanders in tumors.

  2. GBM Suppression Depends on T Cells: In vivo experiments demonstrated that the suppression of GBM by neutrophils depends on T cells and is realized through the interferon (IFN) signaling pathway. This result indicates that the “hybrid” neutrophils in GBM can activate T cells through an MHCII-dependent pathway, thereby inhibiting tumor growth.

  3. Bone Marrow-Originated “Hybrid” Neutrophils: By transplanting labeled skull bone marrow fragments, researchers confirmed that skull bone marrow is the main source of antigen-presenting neutrophils in GBM rather than circulating mature neutrophils. Further analysis shows that immature neutrophils from skull bone marrow are induced to polarize in GBM, gradually displaying antigen-presenting functions.

  4. Therapeutic Potential of AMD3100: The study found that using AMD3100 to enhance migration of skull bone marrow neutrophils significantly prolongs the survival of mice, suggesting potential therapeutic value.

Significance of Results

These findings indicate that GBM utilizes a novel immune evasion mechanism by polarizing bone marrow-derived immature neutrophils into “hybrid” cells with antigen-presenting functions in the tumor microenvironment, thereby activating anti-tumor T cell responses. These results not only reveal the anti-tumor role of TANs in GBM but also highlight the crucial position of skull bone marrow in the GBM immune microenvironment, providing new targets for future GBM immunotherapy.

Research Conclusion and Value

The conclusion of this study is that skull bone marrow can supply immature antigen-presenting cells, including dendritic cell-like “hybrid” neutrophils, to the GBM microenvironment, where they perform anti-tumor immune functions. These findings offer new ideas for immunotherapy in glioblastoma, especially providing evidence supporting the value of drugs enhancing bone marrow neutrophil migration (such as AMD3100) in GBM treatment.

Research Highlights

  1. This study is the first to reveal the immune-supportive role of skull bone marrow in the central nervous system tumor microenvironment, suggesting it could become a clinical treatment target.
  2. The “hybrid” polarization state of TANs has a unique antigen-presenting function, capable of activating T cells through an MHCII-dependent pathway, offering new ideas for tumor immunotherapy.
  3. Using the AMD3100 drug to promote skull bone marrow neutrophil migration can significantly prolong the survival time of mice in GBM models, demonstrating the potential clinical value of enhancing bone marrow neutrophil migration.

Future Outlook

This study points to a significant research direction, further exploring the mechanisms of bone marrow-derived immune cells in central nervous system tumor microenvironments. Future research can delve into the immune role of skull bone marrow in other CNS tumors or diseases, particularly evaluating the efficacy and safety of drugs like AMD3100 in clinical settings.