Related Experiment Video
Updated: Jan 8, 2026
Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts
Published on: September 1, 2018
Fgl2-knockout tumor cells serve as a vaccine inducing long-duration brain-resident memory T cells that reject
Sheng Zhang1, Yining Jin1, Zhiliang Jia1
1Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, USA.
Abstract:
The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients' mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (TRM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this rejection of intracranial challenges in the recipient mice, whereas depleting TRM cells impaired it. Mechanistic studies uncovered that Fgl2 KO impaired the immunosuppressive molecule CD47; reconstitution of CD47 expression in Fgl2-KO tumor cells reversed the protection. Likewise, vaccination with CD47-knockdown tumor cells produced similar effects. Proteomic analysis found that Fgl2-KO-mediated suppression of CD47 occurred through the Src and PKCα pathways; inhibition of either pathway reduced CD47 expression. This study is the first to show that disrupting the Fgl2-CD47 circuit in tumor cells impairs their tumorigenic properties and induces long-term brain TRM cells, thereby providing new strategies for improving the efficacy of currently used whole tumor-cell vaccines.
Insights
A new whole tumor-cell vaccine prevents brain tumors by creating long-lasting immune memory cells. This approach targets the Fgl2-CD47 pathway, offering a novel strategy for brain tumor treatment.
Area of Science:
- Immunology
- Oncology
- Neuroscience
Background:
- Brain tumors, both primary and metastatic, are a leading cause of cancer mortality.
- Current treatments for brain tumors have limited efficacy in preventing recurrence and progression.
- Developing effective strategies to induce long-term anti-tumor immunity in the brain is crucial.
Purpose of the Study:
- To develop a novel whole tumor-cell vaccine capable of inducing long-duration brain-resident memory T (TRM) cells.
- To investigate the role of the Fgl2-CD47 pathway in tumor cell tumorigenicity and immune evasion within the brain.
- To explore new therapeutic strategies for enhancing the efficacy of whole tumor-cell vaccines against brain tumors.
Main Methods:
- Generation of ten Fgl2-knockout (KO) primary and metastatic tumor cell lines using CRISPR/Cas9.
- Vaccination of mice with Fgl2-KO tumor cells followed by intracranial challenge with wild-type (WT) tumor cells.
- Adoptive transfer of brain immune cells from vaccinated mice into naive recipients and depletion of TRM cells to assess immune mechanisms.
- Mechanistic studies involving CD47 reconstitution, CD47 knockdown, proteomic analysis, and pathway inhibition (Src, PKCα).
Main Results:
- Vaccinated mice demonstrated rejection of tumor cell challenges, with over 50% achieving long-term survival.
- Adoptive transfer of immune cells from vaccinated mice conferred tumor resistance to naive recipients, while TRM cell depletion abrogated this protection.
- Fgl2 KO impaired the immunosuppressive molecule CD47, and restoring CD47 reversed the protective effect; CD47 knockdown mimicked these findings.
- Proteomic analysis revealed Fgl2-KO-mediated CD47 suppression occurs via Src and PKCα pathways, with pathway inhibition reducing CD47 expression.
Conclusions:
- Disruption of the Fgl2-CD47 circuit in tumor cells impairs their tumorigenic properties.
- This disruption effectively induces long-term brain-resident memory T (TRM) cells, crucial for tumor rejection.
- The findings present a novel strategy for improving the efficacy of whole tumor-cell vaccines in treating brain tumors.
Related Concept Videos
01:27Tumor Immunotherapy
01:23Cells of the Adaptive Immune Response
01:23Immunological Memory
What is Immunological Memory?
Immunological memory is an integral function of the immune system that allows it to recognize and react more rapidly and effectively to pathogens previously encountered. This feature...
01:40Cell-mediated Immune Responses