Cell: A new target for brain metastasis immunotherapy, Zhang Siyuan's team revealed the regulatory role and mechanism of myelin cells in the central nervous system for brain metastasis

With the development and progress of systematic treatment of in-place tumors, secondary tumor brain metastasis has become more common in clinical practice in recent years, mainly from patients with advanced stages such as melanoma, lung cancer, breast cancer and colon cancer.
development of brain metastasis is the result of the interaction between metastasis of tumor cells (the seed seeds) and the unique immune micro-environment of the central nervous system ("soil" soil).
study found that both myelin cells from the central nervous system-native myeloid cells, CNS-myeloids, and bone marrow-derived myeloid cells (BMDM) were present in the brain metastasis.
previous studies have shown that gliomas and immune cells soaked in brain metastasis tissue have compositional diversity and heterogeneity, and studies using RNA sequencing combined with genealogy tracer technology in animal models of gliomas have found that CNS-myeloids and BMDM are very different in transcription levels.
However, due to the limitations of experimental models and technical means, the specific roles of CNS-myeloids and BMDM in the development of tumor brain metastasis are difficult to distinguish, whether they have different functional characteristics and mechanisms of action, it is not clear.
October 28, 2020, professor Zhang Siyuan of the Department of Biological Sciences at the University of Notre Dame and the Harper Cancer Research Institute presented a research paper entitled "CNS-Native Myeloid Cells Drive I Drive I Drive Suppression in Brain Metastatic Niche through Cxcl10" on Cell.
the study system illustrates the leading role CNS-myeloids plays in promoting the development of brain metastasis by creating a micro-environment for immunosuppression.
this study provides a new research target for immunotherapy of brain metastasis, which has important theoretical value and potential clinical significance.
researchers first looked at tissue pathology specimens, and although brain metastasis tumors originate from different types of primary tumors, Iba-myelin cell immersion is a common and significant feature of a variety of brain metastasis tumor tissues.
in the experimental model of breast cancer brain metastasis, the authors confirmed that myelin cell immersion was closely related to the size and stage of the metastasis.
, high-resolution 3D imaging has been found that impregnated myelin cells have typical distribution patterns and morphological characteristics associated with active.
subsequent mass spectrometrography (CyTOF) analysis found that brain metastasis-soaked immune cells have unique immune cell composition patterns and molecular espressopes compared to normal brain tissue.
authors further used CITE-seq, a new single-cell sequencing technique that can detect surface protein markers and transcription groups at the same time for thousands of different individual cells.
results are the first application of CITE-seq technology in the field of tumor brain metastasis.
Through multi-dimensional protein and RNA data analysis, it was found that brain metastasis-related myelin cells (activated state) showed very different transcription spectra compared to normal brain tissue myelin cells (rest state), which have the characteristics of dispersion and cohesion of gene expression, respectively.
, the results of single-cell sequencing on brain metastasis mouse models were validated in clinical patient brain metastasis and glioma single-cell sequencing data.
in the above-mentioned analysis of high-volume, multi-dimensional single-cell esomoric differences, the researchers found that Cx3cr1 expression was significantly reduced in the myelin cells (CNS-myeloids) of the central nervous system in mice with brain metastasis.
Taking into account the widespread expression of Cx3cr1 in myelin cells, the authors used the Cx3cr1CreERT/:: ROSA26iDTR/?mouse model to give Tamoxifen and diphtheria toxins during brain metastasis of breast cancer, and found that conditional removal of broad-spectrum myelin cells (Figure 1) significantly reduced the number of metastases.
1 experimental design for the conditional removal of broad-spectrum myelin cells is interesting in that the use of the CCR2 gene to knock out myelin cells (BMDM) from bone marrow sources in mice has limited effects on brain metastasis.
results are very different from the previously widely believed role of BMDM in primary brain tumors.
the authors further applied specific removal of CNS-myeloids animal models (Figure 2).
removal of CNS-myeloids can significantly inhibit brain metastasis.
suggests that CNS-myeloids play a leading role in promoting brain metastasis.
a 2-specific solution to the removal of CNS-myeloids, the researchers further found that the targeted removal of Cx3cr1 (Figure 3) in CNS-myeloids could also increase experimental brain metastasis lesions.
then they systematically explored how CNS-myeloids could affect brain metastasis through Cx3cr1.
the authors analyzed the results of single-cell sequencing in depth and found that interferon responses in CNS-myeloids knocked out by Cx3cr1 significantly enhanced and the trending factor Cxcl10 expression was increased.
3 Further mechanism studies of Cx3cr1 knock-out experiments on CNS-myeloids through bone marrow transplantation have found that Cxcl10 inhibits the anti-tumor effect of T cells by collecting the immunosuppressive CNS-myeloids of VISTAHiPD-L1 plus.
given VISTA and PD-L1-medium antibodies in laboratory mice improved T-cell immersion and its immune activity, which in turn significantly reduced the number of brain metastases. In terms of
profile, this study, using a unique genetically engineered mouse model, clever experimental design, combined with clinical patient data and high-volume, multi-dimensional single-cell analysis (Figure 4), reveals that the central nervous system's own myelin cell CNS-myeloids can promote the development of brain metastasis through the specific immunosuppressive microenvironment of the genotypturing factor Cxcl10 signal, which fully illustrates the important regulatory role of tissue immunomic environment in the development process of tumor metastasis.
could provide new strategies for immunotherapy to explore brain metastasis.
Figure 4 Central nervous system myelin cell CNS-myeloids promote the development of brain metastasis through the specific immunosuppressive microenvironment of the coercion factor Cxcl10 signal, Professor Zhang Siyuan's team has made many outstanding achievements in tumor brain metastasis and the study of tumor immune microenvironment using single-cell sequencing in the past two years.
the team reported last August in the journal Nature Communications on a joint immunotherapy strategy to overcome targeted drug-resistant breast cancer under the guidance of a single-cell analysis, and in June this year in Nature Communications on the role of the Rab11b protein-mediated integrative protein cycle in promoting brain metastasis.