Mechanism Study Of The Interaction Between Tumor Associated Macrophages And Lung Adenocarcinoma Cells

As a prominent constituent that is recruited into lung tumor stroma,tumor associated macrophages(TAMs)secrete larger amounts of cytokines to provide a specific microenvironment for cancer progression.Activation of Interleukin-22(IL-22)and associated receptors(IL-22R1)play an important role in tumorigenesis and tumor progression.However,there are widespread controversies about the prognostic significance of TAMs,especially CD163~+TAMs in patients with human primary lung adenocarcinoma.The purpose of this study was to explore the potential correlation between TAMs and lung adenocarcinoma via IL-22/IL-22R1pathway.For the purpose of this study,the improved immunohistochemistry double staining techniques,immunofluorescence,Meta analysis and bioinformatics analysis methods were used.The study was divided into three parts in order to discuss the possible mechanism underneath the interaction between lung adenocarcinoma and TAMs.Firstly,we tend to explore the distribution of TAMs in lung adenocarcinoma tissue and the influence on the prognosis of lung adenocarcinoma.Secondly,proliferation abilities of lung adenocarcinoma will be studied under the effect of TAMs.Thirdly,IL-22/IL-22R1 pathway as an important pathway that is mediated the interaction of TAMs and lung adenocarcinoma to influence the prognosis will be examined.The following main experimental results:1.Accounted for about 80%of the total macrophages in lung adenocarcinoma,M2TAMs enhanced proliferation abilities of lung adenocarcinoma.2.M2 TAMs were risk factors for the prognosis of lung adenocarcinoma.2.1 Kaplan Meier survival analyses showed that the density of M2 TAMs was inversely correlated with the overall survival of lung adenocarcinoma patients.2.2 The distribution of M2 TAMs in the lung adenocarcinoma could serve as an independent prognostic factor by univariate and multivariate Cox regression analysis for overall survival.2.3 Clinical pathological data assay showed that tumor proliferation might be related with the density of M2 TAMs.3.IL-22/IL-22R1 signal pathway was one of the important pathways to mediate the role of M2 TAMs.3.1 The expression profile chip of RNA revealed that IL-22/IL-22R1 pathway was abnormal expression in A549 lung adenocarcinoma cancer cells treated with the conditional medium of M2 TAMs.3.2 Immunofluorescence and immunohistochemical double staining confirmed that TAMs cloud secrete IL-22 independently.3.3 IL22R1 expression was correlated with M2 TAMs in lung adenocarcinoma.4.IL-22R1 was highly expressed in the regions of adenocarcinoma as compared with normal lung tissue that adjacent to carcinoma.5.IL-22R1 expression was influenced on the prognosis in lung adenocarcinoma.5.1 Immunohistochemical results statistically showed that IL-22R1 expression was inversely correlated with clinical prognosis lung adenocarcinoma.5.2 As an independent risk factor,IL-22R1 could pre-judge the prognosis of lung adenocarcinoma patients.5.3 The combinative analysis of IL-22R1 expression and clinicopathological parameters indicated that IL-22R1 was associated with tumor proliferation in lung adenocarcinoma.5.4 Meta-analysis suggested IL-22R1 as a risk factor for the prognosis of lung adenocarcinoma patients.6.M2 TAMs shorten the overall survival of patients by increasing the expression of IL-22R1.Through the description of the results and the combination of the experimental topics,the conclusion is summed up:1.Improved immunohistochemical double-stained staining confirmed that 80%of M2TAMs in tumor-associated macrophages play a role in the development of lung adenocarcinoma in the lung adenocarcinoma stroma.2.It is the first time to reveal that IL-22/IL-22R1 pathway may be one of the key pathways that tumor-associated macrophages affect the biological behavior of lung adenocarcinoma.The study provides us fruitful knowledge and opportunity to further understand the role of TAMs in the malignant biological behavior of lung adenocarcinoma,identify prognostic markers for patients with lung adenocarcinoma,and offer novel therapy strategies target lung adenocarcinoma.