Effect Of Tumor Pre-Metastatic Niche On The Growth And Differentiation Of Bone Marrow-Derived Dendritic Cells In Mice

Tumor metastasis is one of the important characteristics of malignant tumors,and is also the main cause of cancer-related death.Although the phenotype and genetic characteristics of tumor cells determine the characteristics of tumor metastasis,some researchers have proposed that the microenvironment at the target organ of tumor metastasis is also very important for the process of tumor metastasis.In recent years,the new concept of pre-metastatic microenvironment has provided new ideas for preventing tumor metastasis.Prior to tumor cell metastasis,a pre-metastatic microenvironment is first formed at the distal target organ to support metastasis.The establishment of a pre-metastatic microenvironment is a process facilitated by primary tumor-derived factors,tumor mobilization and recruitment of bone marrow-derived cells and multiple types of immune cells.These cells in the pre-metastasis microenvironment reshape the local microenvironment by secreting inflammatory cytokines,growth factors,and angiogenic factors,thereby supporting tumor cell colonization,proliferation,and promoting tumor metastasis.Studies have shown that immune cells in the pre-metastatic microenvironment can play immunosuppressive roles,thereby helping to establish the microenvironment and promoting tumor metastasis.There are a certain number of dendritic cells(DCs)in the pre-metastatic microenvironment.As a full-time antigen-presenting cell,dendritic cells have the ability to stimulate the initial T cells to trigger an immune response.In recent years,more and more studies have shown that in a variety of tumor microenvironments,there are few immunogenic myeloid dendritic cells,and dendritic cells in tumor hosts cannot sufficiently stimulate the immune response,and even immunosuppressive tumor-infiltrating dendritic cells(TIDC)are formed,which helps tumors escape immune recognition and killing.In this study,flow cytometry,qPCR,MLR,ELISA,and Western Blot were used to explore the effects of pre-metastatic microenvironment of B16F10 melanoma-bearing mice on the differentiation and development of mouse myeloid dendritic cells(BMDC).(1)Flow cytometry was used to detect dendritic cells(DC)in the lung pre-metastasis microenvironment of B16F10 tumor-bearing mice during pre-metastasis.It was found that the maturity of dendritic cells in the pre-metastatic microenvironment was suppressed obviously through the detection of cell surface markers related to the maturation of dendritic cells.(2)The tumor pre-metastasis microenvironment was simulated in vivo by using B16F10 tumor-bearing mice,and the differentiation and function of BMDCs was explored.We found that serum from the tumor bearing mice inhibited the differentiation of bone marrow cells into dendritic cells and reduced the expression of BMDC maturation-related factors.The results of qPCR experiments further confirmed that tumor pre-metastasis microenvironment can inhibit the maturation of dendritic cells.(3)MLR and ELISA experiments proved that DCs differentiated in the tumor pre-metastasis microenvironment are immune tolerant,and their ability of stimulating T cells decreased,while the expression of inhibitory inflammatory factors increased.(4)By detecting the activation of immune-related signaling pathways,we found that the expression of NF-?B p65 in dendritic cells in the pre-metastatic microenvironment decreased,and STAT3 expression and STAT3 phosphorylation were enhanced,indicating the maturation and function changes of DCs in the pre-metastatic microenvironment are related to the NF-?B and STAT3 pathways.This study reported that the tumor pre-metastasis microenvironment inhibited the differentiation of dendritic cells and reduced the content of dendritic cells.At the same time,the pre-metastasis microenvironment lead to the dysfunction of dendritic cells and induced them to develop immune tolerance.The results of this paper further explain the mechanism established by the tumor pre-metastasis microenvironment,which will provide certain theoretical and experimental basis for finding new tumor treatment targets.