Related Experiment Video
Updated: Aug 9, 2025
Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
Published on: November 28, 2015
Immune surveillance of brain metastatic cancer cells is mediated by IFITM1
Xiaofei She1,2, Shijun Shen3, Guang Chen1,2
1Cancer Center and Research Institute of Intestinal Diseases, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Abstract:
Brain metastasis, most commonly originating from lung cancer, increases cancer morbidity and mortality. Although metastatic colonization is the rate-limiting and most complex step of the metastatic cascade, the underlying mechanisms are poorly understood. Here, in vivo genome-wide CRISPR-Cas9 screening revealed that loss of interferon-induced transmembrane protein 1 (IFITM1) promotes brain colonization of human lung cancer cells. Incipient brain metastatic cancer cells with high expression of IFITM1 secrete microglia-activating complement component 3 and enhance the cytolytic activity of CD8+ T cells by increasing the expression and membrane localization of major histocompatibility complex class I. After activation, microglia (of the innate immune system) and cytotoxic CD8+ T lymphocytes (of the adaptive immune system) were found to jointly eliminate cancer cells by releasing interferon-gamma and inducing phagocytosis and T-cell-mediated killing. In human cancer clinical trials, immune checkpoint blockade therapy response was significantly correlated with IFITM1 expression, and IFITM1 enhanced the brain metastasis suppression efficacy of PD-1 blockade in mice. Our results exemplify a novel mechanism through which metastatic cancer cells overcome the innate and adaptive immune responses to colonize the brain, and suggest that a combination therapy increasing IFITM1 expression in metastatic cells with PD-1 blockade may be a promising strategy to reduce metastasis.
Insights
Loss of interferon-induced transmembrane protein 1 (IFITM1) promotes brain metastasis by hindering immune responses. Increasing IFITM1 expression combined with PD-1 blockade may reduce brain metastasis.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Brain metastasis, particularly from lung cancer, significantly increases cancer morbidity and mortality.
- The mechanisms underlying metastatic colonization, the most complex step in cancer spread, remain poorly understood.
- Understanding how cancer cells overcome immune surveillance in the brain is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of interferon-induced transmembrane protein 1 (IFITM1) in brain metastasis of lung cancer.
- To elucidate the mechanisms by which IFITM1 influences the brain's immune microenvironment and cancer cell evasion.
- To explore the therapeutic potential of targeting IFITM1 in combination with immune checkpoint inhibitors.
Main Methods:
- Genome-wide CRISPR-Cas9 screening in vivo to identify genes involved in brain colonization.
- Analysis of IFITM1 expression in incipient brain metastatic cells.
- Assessment of microglia activation, CD8+ T cell activity, and immune cell interactions.
- Correlation of IFITM1 expression with clinical trial data of immune checkpoint blockade therapy.
- Evaluation of IFITM1's effect on PD-1 blockade efficacy in mouse models.
Main Results:
- Loss of IFITM1 was found to promote brain colonization of human lung cancer cells.
- High IFITM1 expression in metastatic cells enhances microglia activation and CD8+ T cell cytolytic activity via MHC class I.
- Activated microglia and CD8+ T cells cooperate to eliminate cancer cells through interferon-gamma release, phagocytosis, and T-cell-mediated killing.
- IFITM1 expression positively correlated with response to immune checkpoint blockade therapy in human trials.
- IFITM1 enhanced the efficacy of PD-1 blockade in suppressing brain metastasis in mice.
Conclusions:
- Metastatic cancer cells utilize IFITM1 to evade innate and adaptive immune responses in the brain.
- IFITM1 plays a critical role in modulating the brain's immune microenvironment to facilitate metastatic colonization.
- Combination therapy involving enhanced IFITM1 expression in metastatic cells and PD-1 blockade presents a promising strategy for reducing brain metastasis.
Related Concept Videos
01:27Tumor Immunotherapy
02:17The Tumor Microenvironment