Role And The Mechanism Of Bone Marrow-derived Suppressor Cells On Lung Adenocarcinoma Progression

Part 1 The distribution of myeloid-derived suppressor cells(MDSCs)and their subpopulations in patients with primary lung adenocarcinoma and the role of NF-?B signaling pathway in promoting tumor progression in MDSCsObjective: The aim of this study was to investigate the distribution of MDSCs and their subtypes in lung cancer tissues,lung cancer tissues,and lung cancer tissues,and to investigate the role of NF-?B signaling pathway in promoting tumor progression.Methods: From August 2017 to January 2018,53 patients with primary adenocarcinoma of the lung in the Department of Esophageal Oncology and Lung Oncology,Tianjin Medical University Cancer Center were enrolled.Fresh tissue specimens were collected.Flow cytometry was used to detect the proportion of MDSCs and their subtypes,and the relationship between them and clinicopathological features was analyzed.The lungs were detected by immunofluorescence.Colocalization of CD33 with Arg1,i NOS and NF-?B in adenocarcinoma,near-cancerous and distant lung tissues.Results: 1.The proportion of total MDSCs in normal lung tissues and adjacent tissues is higher than the proportion of total MDSCs in cancer tissues;the proportion of M-MDSC in normal lung tissues of lung adenocarcinoma patients is comparable to that in adjacent tissues and cancer tissues.The proportion of PMN-MDSCs cells in normal lung tissue of lung adenocarcinoma patients was similar to that of PMN-MDSCs cells in paracancerous tissues;the proportion of PMN-MDSCs cells in adjacent tissues was significantly higher than that of PMN-MDSCs cells in cancer tissues;2.The proportion of M-MDSC cells in normal lung tissue of patients with ground glass nodules was slightly higher than that in adjacent tissues.The proportion of PMN-MDSCs cells in adjacent tissues was significantly higher than that in cancer tissues.3.In lung adenocarcinoma with non-ground glass nodules,the proportion of total MDSCs in normal lung tissue was slightly higher than that in adjacent tissues;the ratio of PMN-MDSCs in cancer tissues is higher than that in cancer tissues.4.The proportion of MDSCs in normal lung tissue of non-ground glass nodules was slightly higher than that of ground glass nodules.The proportion of MDSCs in adjacent tissues of non-ground glass nodules was slightly higher than that of ground glass lung adenocarcinoma.Among the lung adenocarcinoma with non-ground glass nodules,the proportion of MDSCs in normal lung tissue of lung adenocarcinoma with diameter more than 2cm was higher than that in diameter less than 2cm;5.The proportion of MDSCs in normal lung tissue of lung adenocarcinoma with pathological high risk factors was higher than that with low risk factors.The proportion of MDSCs in adjacent tissues of lung adenocarcinoma with pathological high risk factors was higher than that with low risk factors.6.The proportion of MDSCs in lung cancer tissues of smoking patients was higher than that of non-smokers.The number of MDSCs in adjacent tissues was correlated with the percentage of immature granulocytes in peripheral blood.The proportion of PMN-MDSCs in cancer tissues was correlated with the absolute value of immature granulocytes.7.CD33 and Arg1,CD33 and i NOS,CD33 and NF-?B were co-localized in cancer tissues,near-cancerous lung tissues and distant lung tissues.MDSCs and lymphocytes in lung cancer tissues and distant cancer tissues were significantly higher than those in cancer tissues.Conclusion: The proportion of total MDSCs in distant lung and near-cancerous lung tissues is higher than that in cancer tissues,and the proportion is related to the factors such as ground glass nodules,tumor size,pathological risk factors and smoking.Related;MDSCs cells play an important role in tumorigenesis,and activation of NF-?B signaling pathway is the main mechanism by which MDSCs promote tumorigenesis.Part 2 Tumor necrosis factor promotes lung cancer progression by NF-?B signaling activation of MDSCsObjective: To investigate the effects of MDSCs in tumor-bearing mice on tumor cells in vitro and to elucidate the mechanism of TNF-mediated MDSCs in promoting lung cancer.Methods:: MDSCs were sorted by magnetic bead sorting from normal mice and tumor-bearing mice,and co-cultured with tumor cells.CCK8 method was used to detect tumor proliferation;Boedden chamber was co-cultured with tumor cells in vitro.The effects of MDSCs on tumor invasion and migration were observed.The levels of tumor necrosis factor-?(TNF-?)in co-culture supernatants were detected by ELISA.The mouse model of lung adenocarcinoma with TNF-overexpressed K-ras G12 D gene mutation was studied by flow cytometry,enzyme-linked immunosorbent assay,Western Blot and immunohistochemistry to study the infiltration of TNF on MDSCs and its specificity.Molecular regulation mechanism.Result: 1.MDSCs have no proliferative effect on tumor cells;2.The spleen and lung MDSCs of tumor-bearing mice and normal mice can promote the invasion ability of tumor cells;3.The spleen and lung MDSCs of tumor-bearing mice can promote the migration ability of tumor cells;the spleen MDSCs of normal mice can promote the migration ability of tumor cells.4.The TNF-? levels in the spleens of normal mice,the spleens of the tumor-bearing mice,and the MDSCs of the lungs were higher than those of the control group.5.TNF recruits MDSCs to infiltrate and possibly activates MDSCs via NF-?B signaling,resulting in increased IL-6 secretion,activating STAT3 signaling pathways in tumor cells,promoting tumor proliferation and promoting angiogenic microenvironment formation.Conclusion: TNF can promote the development of lung cancer by recruiting and activating MDSCs through NF-?B signaling,which results in increased IL-6 secretion,activating STAT3 signaling pathway in tumor cells,promoting tumor proliferation and promoting angiogenic microenvironment.