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Objective:To analyze the expression of targeting protein for Xklp2 (TPX2) in kidney renal clear cell carcinoma (KIRC) and its clinical significance.Methods:The postoperative tissue samples of 54 patients with KIRC admitted to the Department of Urology, the First Affiliated Hospital of Bengbu Medical College from July 2017 to June 2019 were collected. Immunohistochemistry was used to detect the protein expression of TPX2 in renal carcinoma and paracancerous tissues. The difference of TPX2 mRNA expression between KIRC tissues and normal tissues was analyzed by using the TIMER database, which verified the immunohistochemical results. The UALCAN database and the Kaplan-Meier plotter database were used to analyze the relationship between TPX2 mRNA expression and clinical stage, molecular subtypes, lymph node metastasis, and prognosis of patients with KIRC. The protein interaction network was constructed by STRING database to obtain TPX2-related proteins, and the genes corresponding to the related proteins were enriched for the KEGG pathway. The relationship between TPX2 expression and immune cell infiltration and the immune checkpoint was studied by using the TIMER database.Results:Immunohistochemical results showed that the positive expression rate of TPX2 protein was 48.15% (26/54) in cancer tissues, which was higher than that in paracancerous tissues (20.37%, 11/54) ( χ2=9.25, P=0.002). The results of bioinformatics analysis showed that TPX2 mRNA expression was significantly up-regulated in KIRC [cancer tissue: 1.89 (1.49, 2.42), normal tissue: 0.35 (0.24, 0.57), U=2 297.00, P<0.001]. The expression of TPX2 mRNA was related to the clinical stage ( χ2=34.36, P<0.001), molecular subtypes ( χ2=30.15, P<0.001), and lymph node metastasis status ( χ2=27.21, P<0.001) of KIRC patients. The 5-year survival rate (53.80%) in patients with high TPX2 expression was lower than that in patients with low TPX2 expression (74.40%, χ2=18.87, P<0.001). STRING database protein interaction network construction obtained 20 TPX2-related proteins, and the genes corresponding to the related proteins were enriched in the cell cycle. The expression of TPX2 was positively correlated with B cells ( r=0.30, P<0.001), CD8 + T cells ( r=0.23, P<0.001), CD4 + T cells ( r=0.18, P<0.001), macrophages ( r=0.20, P<0.001), neutrophils ( r=0.31, P<0.001), dendritic cells ( r=0.39, P<0.001) infiltration and most of its biomarkers (all P<0.05). It was positively correlated with immune checkpoint PD-1 ( r=0.31, P<0.001) and CTLA-4 ( r=0.27, P<0.001), but not correlated with PD-L1 ( r=0.07, P=0.146) . Conclusion:TPX2 is highly expressed in KIRC and is closely associated with poor prognosis. It is expected to be a new therapeutic target for KIRC.
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PD-1 and PD-L1 together constitute the stimulus signaling pathway of adaptive immune response, which has been widely used in the research on the mechanism of tumor immune escape and tumor therapy. At the same time, its signaling pathway has been proved to be closely associated with the immune escape of hepatic echinococcosis. This article reviews the chemical structures of PD-1 and PD-L1, the mechanism of the PD-1/PD-L1 signaling pathway, and the role of the PD-1/PD-L1 signaling pathway in immune escape of hepatic echinococcosis, i.e., the PD-1/PD-L1 signaling pathway is involved in immune escape of hepatic echinococcosis under three theories, so as to explore the immune escape of hepatic echinococcosis from a new perspective and provide a basis and ideas for the diagnosis and treatment of hepatic echinococcosis.
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ObjectiveTo determine whether HBV DNA polymerase is associated with T-cell failure and thus mediates the immune escape of HBV-related hepatocellular carcinoma （HCC） tumor cells， and to investigate the specific molecular mechanisms. MethodsLiver cancer cell lines Huh7 and HepG2 stably transfected with HBV DNA polymerase expression plasmid with Flag （Flag-HBV-P） and intercellular adhesion molecule-1 （ICAM1） were co-cultured with Jurkat cells， and MTT assay， qRT-PCR， and ELISA were used to measure Jurkat cell proliferation， activation （CD69 expression）， and secretion of the cytokine IFN-γ. RNA-seq was used to screen for differentially expressed immune-associated molecules between stably transfected cell lines and control cells， and mRNA half-life and protein half-life assays were used to determine the specific levels of the immune-associated molecules that were affected by HBV DNA polymerase. Related websites were used to predict the transcription factors that may bind to the promoter region of this immune-associated molecule， Western blot was used to verify the effect of transcription factors on the immune-associated molecule， and rescue experiment was used to determine whether HBV DNA polymerase affects the expression level of the immune-associated molecule through this transcription factor. The independent-samples t test was used for comparison between two groups. ResultsThe experimental group had significant reductions in Jurkat cell proliferation， activation， and cytokine secretion compared with the control group （all P<0.01）. Compared with the control group， the experimental group （Huh7 and HepG2 cell lines） had significant reductions in the mRNA and protein expression levels of ICAM1 （all P<0.01）. Website prediction identified the ICAM1 promoter and preliminarily highlighted NFKB1， RELA， and STAT3. Compared with the control group， the experimental group （Huh7 and HepG2 cell lines） had a significant reduction in the protein expression level of p65 （all P<0.01）. After p65 overexpression， there was a significant increase in the protein expression level of ICAM1， and after the expression of p65 was reduced， there was a significant reduction in the protein expression level of ICAM1 （all P<0.01）. In the rescue experiment， there was no significant difference in the protein expression level of ICAM1 between the control group and the experimental group after p65 overexpression （all P>0.05）. After the overexpression of ICAM1， there were no significant differences in the proliferation， activation， and cytokine secretion of Jurkat cells between the control group and the experimental group （Huh7 and HepG2 cell lines） （all P>0.05）. ConclusionHBV DNA polymerase downregulates the level of ICAM1 to mediate HCC immune escape by inhibiting the expression of p65 in NF-κB.
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Lactic acid, a widespread metabolite in the tumor microenvironment, is mainly produced by tumor cells that undergo aerobic glycolysis. Lactic acid is closely related to the occurrence and development of tumor. It not only serves as a substrate to supply energy to tumor cells, but also acts as a signaling molecule to activate multiple pathways to promote invasive and metastasis, angiogenesis and immune escape of tumor cells. In-depth research on the mechanism of action of lactic acid in the occurrence and development of tumor and related therapeutic progress will help to find drug targets for treatment of tumor and improve prognosis of patients.
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Objective:This study aims to reveal the special immune infiltrating environment and possible immune escape mechanism of giant cell tumor of bone through single-cell sequencing data.Methods:The fresh samples obtained from 4 patients with primary giant cell tumor of bone from January 2018 to December 2021 were collected, and single-cell transcriptome sequencing was performed on the 10X platform to explore the characteristics and immune environment of giant cell tumor of bone by using t-distributed stochastic neighbor embedding ( t-SNE). The main cell types and signal pathways of immune cell regulation and function in giant cell tumor of bone were observed by cell communication analysis. Results:Cell clustering, the definition of basic cell types, the classification of immune cells, and the mutual regulatory relationship between cell types were analyzed for 35 643 single-cell data from 4 giant cell tumor samples of bone. It was found that giant cell tumor of bone was composed of 9 basic cell types, in which the immune cells were mainly CD8 + T cells (51%) and the non-immune cells were mainly fibroblast like spindle stromal cells (74%). The immune infiltration of giant cell tumor of bone is dominated by cytotoxic CD8 + T cells and lacks exhausted CD8 + T cells. CD4 + T cells are characterized by high expression of immune checkpoint genes CTLA4 and TIGIT. In giant cell tumor of bone, immune cells mainly act on multinucleated osteoclast like giant cells through PARs and CCL signaling pathways, but not stromal cells. Conclusion:This study defined the main cell types of giant cell tumor of bone through single cell sequencing data, and further revealed the composition characteristics of its immune infiltration, and found that the target of its immune cells was mainly multinuclear osteoclast like giant cells, which provided effective information for further understanding the occurrence and development of giant cell tumor of bone.
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Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are important co-inhibitory molecules, while regulatory T cells (Tregs) are important suppressor cells. The increase of them in tumor microenvironment is closely related to tumor immune escape and tumor development. PD-L1 plays an important role in the development and function of Tregs. The application of PD-1/PD-L1 blockade also affects the proliferation and function of Tregs, which further participates in the occurrence of drug resistance and hyperprogressive disease. Further understanding of the role and correlation of PD-L1 and Tregs in tumor immunity and immunotherapy can provide new ideas for improving the efficacy of PD-1/PD-L1 blockade.
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Tumor microenvironment plays an important role in the formation and development of tumors, and the acidity is one of the remarkable features of tumor microenvironment. Due to excessive proliferation of tumor cells and abnormal structure of tumor blood vessels, the tumor tissues are usually in a hypoxia state, leading to changes in the metabolic processes of tumor cells. Compared with the normal tissues which mainly rely on aerobic oxidation to obtain energy, the metabolism of tumor cells dominatingly depends on the anaerobic glycolysis. Therefore, the lactate acid produced by glycolysis and the carbon dioxide produced by respiration together result in the acidification of tumor microenvironment (TME), and affects many aspects of tumorigenesis and development. This review focuses on the formation mechanism of tumor acidic microenvironment and its impacts on tumor progression, including tumor immunity, invasion, autophagy and resistance to anti-cancer treatment.
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Malignant tumor is one of the important diseases that affect human health. The occurrence and development of tumors are closely related to the imbalance of immune function. When the body’s immune function is low or suppressed, the traditional treatment methods can not improve the survival of cancer patients. Therefore, improving immunity and reducing immune tolerance have become one of the hotspots in anti-tumor research. Studies have shown that Chinese medicine can regulate T lymphocytes, dendritic cells, natural killer cells and macrophages, so as to improve the body’s immunity and inhibit the occurrence and development of tumors. This article reviews the role of traditional Chinese medicine in regulating tumor immunity and inhibiting tumor progression.
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The complement system is an important part of the innate immune system. More evidence showed that the function of complement was not only limited to the elimination of pathogens and other risk factors from the body but also affected the immune escape mechanism of the tumor through different activating pathways. Because of the complex and important role of complement in the tumor, this review expounds the mechanism of complement system participating in immune escape of the tumor from three aspects: complement inherent components, complement activation products and complement regulatory proteins. Additionally, these mechanisms are expected to provide a new application of complement in tumor immunotherapy with immune checkpoint inhibitors.
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The complement system is an important part of the innate immune system. More evidence showed that the function of complement was not only limited to the elimination of pathogens and other risk factors from the body but also affected the immune escape mechanism of the tumor through different activating pathways. Because of the complex and important role of complement in the tumor, this review expounds the mechanism of complement system participating in immune escape of the tumor from three aspects:complement inherent components, complement activation products and complement regulatory proteins. Additionally, these mechanisms are expected to provide a new application of complement in tumor immunotherapy with immune checkpoint inhibitors.
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Exosomes belong to microvesicle structures widely distributed in many body fluids secreted by a variety of living cells, which can carry biological information molecules such as nucleic acids, proteins and lipids derived from parental cells, being the communication carriers among cells. Exosomes play a critical role in cancer progression and participate in tumor cell proliferation, tumor migration, immune escape and angiogenesis. In hematologic system, exosomes involve in the crosstalk between leukemia cells and the surrounding environment, promote the formation of leukemia microenvironment and act as immunomodulators, which will be a potential direction for its therapeutic research. This article reviews the biological characteristics of exosomes and their roles in leukemic tumor microenvironment and immune regulation.
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B7-H6 has been discovered as a new member of the B7 family in recent years, it can specifically bind to the NKp30, an activated receptor of natural killer (NK) cells to mediate NK cells' tumor immunity killing effect. B7-H6 expression is upregulated in a wide variety of malignant tumor cells, but expression deficiency in normal tissue is detected. The intrinsic mechanism of B7-H6 regulation has been explored, and the treatment targeting B7-H6 has achieved a good effect in animal experiments, which shows a wide prospect of clinical application. This paper summarizes the latest progress of B7-H6 molecule in malignant tumors.
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Programmed death ligand-1 (PD-L1) is highly expressed on most tumor cells,and it interacts with programmed death-1 (PD-1) on the surface of immune cells,which mainly inhibits T cell proliferation and plays an important role in tumor immune escape.The studies find that PD-1/PD-L1 pathway can promote tumor cell glycolysis and epithelial-mesenchymal transition,and can induce PD-L1 expression on macrophages and enhance immunosuppression in tumor microenvironment.Therefore,PD-1/PD-L1 is considered to be an important immunoassay point,and a series of anti-PD-1 and PD-L1 antibodies,such as pembrolizumab,nivolumab,atezolizumab,durvalumab and avelumab,have clinically shown good effects.Further understanding of its mechanism may provide new ideas for the treatment of malignant tumors such as lung tumors.
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Objective@#To investigate the mechanism of apoptosis of CD8+T lymphocyte in peripheral blood of patients with hepatocellular carcinoma (HCC).@*Methods@#The proportion and apoptosis of peripheral blood CD8+T lymphocytes in 30 healthy controls, 30 patients with cirrhosis and 60 HCC patients were detected by Flow cytometry, and the expression of Fas on the surface of CD8+T lymphocytes was reported. The differences between groups were compared using independent sample t-test, and data of variance were tested with Mann-Whitney U non-parametric test, P < 0.05 was considered statistically significant.@*Results@#The proportion of CD8+T lymphocytes in peripheral blood of patients with HCC was 26.4% ± 9.2%, higher than that of 24.5% ± 7.1% in cirrhosis (t = 0.783, P = 0.489), and and healthy control 19.7% ± 4.7% (t = 2.920, P = 0.004). The proportion of apoptotic CD8+T lymphocytes in peripheral blood of HCC patients was 25.3% ± 6.5%, of the total CD8+T lymphocytes, which was significantly higher than that of healthy controls 12.1%±6.5% (t = 7.555, P < 0.001) and cirrhotic 13.6% ± 5.8% (t = 5.213, P < 0.001), the differences were statistically significant. The proportion of Fas+CD8+T lymphocytes in the HCC group was 62.2% ± 18.5%, higher than that in the healthy control group 42.6%±16.5% (t = 4.127, P < 0.001) and 46.1% ± 14.5% (t = 2.561, P < 0.01)of the cirrhosis group, the differences were statistically significant. Fas expression was positively correlated with the apoptosis of CD8+T lymphocytes (r 2 = 0.113, P < 0.05).@*Conclusion@#The proportion of CD8+T lymphocytes in peripheral blood of patients with HCC is higher than that of healthy controls, but the proportion of CD8+T lymphocyte apoptosis based on Fas/FasL pathway increased, which may be an important mechanism for tumor cell immune escape.
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Exosomes are a type of nanoscale vesicles that are actively secreted by various type of cells, and are considered as a new way of cell communication. The exosomes can shuttle bioactive molecules including proteins, lipids, miRNAs and mRNAs from one cell to another, resulting in the exchange of genetic information between cells and the reprogramming of recipient cells. Many evidences show that tumor cells can secrete a large amount of exosomes and regulate tumor progression,metastasis,immune escape, resistance and many other aspects through a variety of ways. In the tumor microenvironment, exosomes transmit between tumor cells,immune cells,and stromal cells,contributing to the escape from immune surveillance.This review summarizes recent advances in exosomes in tumor immune escape.
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Tumor-derived exosomes (TEXs) are small membrane vesicles secreted by tumor cells.They contain various proteins and RNA which make they serve as functional mediators in cell interaction.TEXs can alter the components of extracellular matrix and induces epithelial-mesenchymal transition of tumor cells,which enhance the invasiveness of tumor cells.TEXs regulate immunity through multiple pathways,allowing circulating tumor cells to escape immune surveillance.TEXs promote pre-metastatic microenvironment in target organ before metastasis and induce angiogenesis after circulating tumor cells colonization.Understanding the role and mechanism of TEXs in this process can effectively block relevant signaling pathways which may provide new targeted therapies for clinic.
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Aromatic hydrocarbon receptor (AhR),an intracellular receptor,contains multiple ligand binding sites.Various ligands of AhR are divided into exogenous and endogenous ligands according to the origination.Different ligands bind and activate AhR,regulating the transcription of downstream target genes,especially CYP1 from Cypcytochrome P450 gene family,which plays an essential role in different pathological problems,as well as in the normal development and function of organism.Kynurenine(Kyn),a key metabolic product of tryptophan (Trp),metabolic products of which are major types of endogenous ligands of AhR,has an impact on adaptive immune by manipulating the polarization and activity of immunocytes.Kyn has been focus for its supressive effect in anti-tumor immunity and raised concern recently for its intriguing role in allograft immunoregulation.Research advances in the role of AhR in immunoregulation related to tryptophan metabolism will be illustrated in this review in detail.
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IDO1 (indoleamine 2,3-dioxygenase 1) is one of the most significant checkpoint in tumor immunology. Numerous studies indicates that IDO1 is abnormally expressed in breast cancer, colorectal cancer, liver cancer and other tumor tissues, participating in tumor immune escape through multiple pathways. This review is prepared to elucidate the biological function of IDO1, highlight its pivotal role in tumor evasion, and summarize IDO1 inhibitors in the clinical trials.
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Complement system is a central part of the innate immune response that has developed as a first defense against non-self cells.Complement activation has traditionally been considered part of the body's immunosurveillance against cancer.However,recent studies have demonstrated that activated components of the complement system can assist the escape of tumor cells from immunosurveillance,promote angiogenesis,activate mitogenic signaling pathways,sustain cellular proliferation and insensitivity to apoptosis,and participate in tumor cell invasion and migration.This review reviewed the progress of complement activation and tumor immune surveillance and immune evasion,in order to provide a new strategy for antitumor immunotherapy.
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Circulating tumor cells (CTCs) are a kind of tumor cells disseminated in the peripheral blood circulation due to spontaneous operation, diagnosis or treatment. CTCs have been regarded as crucial source of tumor recurrence and metastasis. The recent studies show that CTCs can survive in circulatory system through overcoming mechanical damage of blood shear stress, evading immune destruction, and resistance to anoikis and systemic chemotherapy drugs. In this paper, the possible survival mechanisms involved in CTCs formation and migration are reviewed according to their biological characteristics and blood microenvironment, while the latest progress in the novel strategies for tumor treatment targeting CTCs is discussed.