Affiliation:
1. Huazhong University of Science and Technology Tongji Medical College First Clinical College Union Hospital
2. Huazhong University of Science and Technology Tongji Medical College First Clinical College Union Hospital Tumor Center
Abstract
Abstract
Background
Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Our previous study demonstrated that radiotherapy activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance.
Methods
We screened genes related to NSCLC brain metastasis through transcriptome analysis. We analyzed the effects of targeted blockade of the MIF/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF/CD74 axis on the growth of brain metastasis.
Result
Our findings reveals that the macrophage migration inhibitory factor (MIF) was identified to be a highly expressed gene in the patients with brain metastasis and further found to be associated with shorter survival time. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1α dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglial M1 polarization in vivo.
Conclusions
Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC. Understanding the impact of MIF/CD74 axis on microglia during radiotherapy provides important insights into the dynamic changes and related relationships of microenvironment during tumor treatment. These insights may provide potential strategies for improving radiation resistance
Publisher
Research Square Platform LLC