1/31/2024 0 Comments Kevin renderman brain tumorOur current study detects chronic low-level type I interferon (IFN) activation in the cancer cells and the reciprocal astrocytes throughout the brain metastatic process. Therefore, immune cells are an important component in the brain microenvironments that regulate metastatic outgrowth. Retrospective studies indicate that multiple immunotherapies improved overall survival in brain metastasis patients 26, 27, 28, 29, 30. ![]() The brain has an immune-specialized rather than immune-privileged environment under pathological conditions 25. Patients with active brain metastatic lesions were invariably excluded from immunotherapy clinical trials. The immunotherapies were expected to be ineffective in brain tumors due to the limited drug delivery and immune responses in the brain. Thus, the brain used to be defined as an immune-privileged organ. The specialized brain–blood barrier (BBB) provides a highly selective permeability barrier to the entrance of immune cells 24. Our knowledge on the immune cells in brain metastatic lesions is very limited. Modified by the tumor microenvironment, these flexible myeloid cells elicit immunosuppressive functions to promote tumor growth 18, 19, 20, 21, 22. ![]() Tumor-associated macrophages are either differentiated from recruited monocytes and M-MDSC from circulation or modified from tissue residential macrophages 21, 22, 23. Myeloid-derived suppressor cells (MDSC), including monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC), are currently defined as pathologically activated monocytes and neutrophils, respectively 18, 19, 20. Multiple myeloid subpopulations have been shown to facilitate carcinogenesis and metastasis. Immune cells are the most studied microenvironmental cells in cancer. Interactions between cancer cells and astrocytes in the brain microenvironment are dynamic, complex, and far more inextricably linked. On the other hand, astrocytes have been shown to facilitate cancer cell survival, growth, and migration at different stages of metastatic outgrowth 10, 11, 12, 13, 14, 15, 16, 17. On one hand, astrocytes release the killing factor in the microenvironment to induce cancer cell apoptosis 10. Of note, the versatile astrocytes have diverse functions. Metastatic cancer cells induce astrogliosis by activating the surrounding astrocytes, marked by increased glial fibrillary acidic protein (GFAP) expression and cellular processes 8, 9. In the brain, astrocytes are the most abundant stromal cells. Meanwhile, the cancer cells actively modify the stromal cells to create a metastasis-specific microenvironment 6, 7. Upon arrival in the distal organs, invaded cancer cells passively adapt to the new microenvironment. ![]() Therefore, there is an urgent need to overcome this challenge by identifying mechanistic insights, prognostic markers, and novel therapeutic targets in brain metastasis studies. Consequently, brain metastasis becomes a significant clinical challenge in patients who have survived the primary tumor and extracranial metastases. Despite significant improvements in cancer treatment, current therapies have limited efficacy in brain metastases 1, 2, 3, 4, 5. The most common sources of brain metastasis are lung, breast carcinoma, and melanoma. Moreover, this work expands our understandings on the interactions between cancer-activated astrocytes and immune cells in brain metastasis.īrain metastasis is the most ominous form of relapse in cancer patients, which is associated with poor prognosis and almost invariably lethal. ![]() Our study clarifies a pro-metastatic effect of type I IFN in the brain even though IFN response has been considered to have anti-tumor effects. Lastly, genetically or pharmacologically inhibiting C-C Motif Chemokine Receptor 2 (CCR2) reduces brain metastases. The correlation between CCL2 and monocytic myeloid cells is confirmed in clinical brain metastasis samples. Mechanistically, IFN signaling in astrocytes activates C-C Motif Chemokine Ligand 2 (CCL2) production, which further increases the recruitment of monocytic myeloid cells. We further confirm that the IFN response in astrocytes facilitates brain metastasis. Here, we demonstrate that cancer-activated astrocytes create a sustained low-level activated type I interferon (IFN) microenvironment in brain metastatic lesions. Metastasis is the consequence of favorable interactions between invaded cancer cells and the microenvironment. Cancer metastasis to the brain is a significant clinical problem.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |