Initial Study on Immune Escape Mechanism of Mouse Acute Myelomonocytic Leukemic Cell Line WEHI-3

Objective： To investigate the expression of Fas, Fas ligand （FasL） and CD80 on the cell surface of mouse acute myelomonocytic leukemia cell line WEHI-3 and the function of FasL. Methods： The expression of Fas, FasL and CD80 was detected on WEHI-3 cell surface by flow cytometry. Simultaneously the function of FasL was determined by Thymidine （^3H-TdR） Incorporation. Results： The expression of CD80 and Fas on WEHI-3 cell surface was 5.06%±0.41% and 6.75%±2.31% （n=5） respectively, and the expression of FasL was up to 63.73%±5.23% （n=5）. The apoptotic rate of YAC-1 cells was 26%±4.5%, 35%±3.2% and 43%±2.7% （n=5） respectively when WEHI-3 （effector cell, E） and Fas^＋ YAC-1 cells （target cell, T） were cultured in the ratio of 3：1, 10：1 and 30：1. Conclusion： WEHI-3 cells express high FasL, low Fas and CD80, and can induce apoptosis of Fas^＋ YAC-1 cells.

Possible mechanisms associated with immune escape and apoptosis on anti-hepatocellular carcinoma effect of Mu Ji Fang granules

BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common digestive system cancers with high mortality rates worldwide.The main ingredients in Mu Ji Fang Granules(MJF)are alkaloids,flavonoids,and polysaccharides.MJF has been used in the clinical treatment of hepatitis,cirrhosis and HCC for more than 30 years.Few previous studies have focused on the mechanism of MJF on tumor immunology in the treatment of HCC.AIM To explore the mechanism of action of MJF on tumor immunology in the treatment of HCC.METHODS The absorbable ingredients of MJF were identified using Molecule Network related to High Performance Liquid Chromatography-Electron Spray Ionization-Time of Flight-Mass Spectrometry,and hub potential anti-HCC targets were screened using network pharmacology and pathway enrichment analysis.Forty male mice were randomly divided into the Blank,Model,and MJF groups(1.8,5.4,and 10.8 g/kg/d)following 7 d of oral administration.Average body weight gain,spleen and thymus indices were calculated,tumor tissues were stained with hematoxylin and eosin,and Interferon gamma(IFN-γ),Tumor necrosis factorα(TNF-α),Interleukin-2,aspartate aminotransferase,alanine aminotransferase,alpha-fetoprotein(AFP),Fas,and FasL were measured by Enzyme-linked Immunosorbent Assay.Relevant mRNA expression of Bax and Bcl2 was evaluated by Real Time Quantitative PCR(RTqPCR)and protein expression of Transforming growth factorβ1(TGF-β1)and Mothers against decapentaplegic homolog(SMAD)4 was assessed by Western blotting.The HepG2 cell line was treated with 10 mg/mL,20 mg/mL,30 mg/mL,40 mg/mL of MJF,and another 3 groups were treated with TGF-β1 inhibitor(LY364947)and different doses of MJF.Relevant mRNA expression of TNF-α,IFN-γ,Bax and Bcl2 was evaluated by RT-qPCR and protein expression of TGF-β1,SMAD2,p-SMAD2,SMAD4,and SMAD7 was assessed by Western blotting.RESULTS It was shown that MJF improved body weight gain and tumor inhibition rate in H22 tumorbearing mice,protected immune organs and liver function,reduced the HCC indicator AFP,affected immunity and apoptosis,and up-regulated the TGF-β1/SMAD signaling pathway,by increasing the relative expression of TGF-β1,SMAD2,p-SMAD2 and SMAD4 and decreasing SMAD7,reducing immune factors TNF-αand IFN-γ,decreasing apoptosis cytokines Fas,FasL and Bcl2/Bax,and inhibiting the effect of LY364947 in HepG2 cells.CONCLUSION MJF inhibits HCC by activating the TGF-β1/SMAD signaling pathway,and affecting immune and apoptotic cytokines,which may be due to MJF adjusting immune escape and apoptosis.

Role of immune escape in different digestive tumours

A counterbalance between immune cells and tumour cells is key to fighting tumours,and immune escape is an important mechanism for the survival of tumour cells in the body.Tumor cells and their cytokines impair the activity of T cells,NK cells,macrophages and other immune cells through various ways,and change the expression of their own surface antigens so as to avoid the clearance of the immune system.Changes in major histocompatibility complex molecules,high expression of programmed death-ligand 1,and the presence of immunosuppressive cells in the tumor microenvironment(TME)are main means by which tumors impair the function of immune cells.During the development of tumours of the digestive system,different mechanisms acting on tumour cells,the TME,and immune cells lead to immune escape and promote tumour progression.In this paper,the mechanisms of immune escape in tumour cells of the digestive system are reviewed to provide a theoretical basis for the immunotherapy of gastrointestinal tumours.

Investigation of immune escape-associated mutations of hepatitis B virus in patients harboring hepatitis B virus drug-resistance mutations

It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen(HBsAg)are associated with nucleoside/nucleotide analog resistance.AIM To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations.METHODS In total,19440 patients with chronic hepatitis B virus infection,who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017,were enrolled.As determined by sequence analysis,6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations.Phenotypic analyses were performed to evaluate HBsAg production,replication capacity,and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V.RESULTS The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations.In particular,these mutations were sQ101H/K/R,sS114A/L/T,sT118A/K/M/R/S/V,sP120A/L/Q/S/T,sT/I126A/N/P/S,sM133I/L/T,sC137W/Y,sG145A/R,and sA159G/V.Among these,sA159V was detected in 1.95%(136/6982)of patients with resistance mutations and 1.08%(134/12,458)of patients lacking resistance mutations(P<0.05).The coexistence of sA159V with lamivudine(LAM)and entecavir(ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance.HBsAg production was significantly lower and the replication capacity was significantly higher,without a significant difference in LAM/ETV susceptibility,in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts.CONCLUSION In summary,we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations.sA159V might increase the fitness of LAM/ETV-resistant mutants under environmental pressure in some cases.

Single-cell RNA-seq reveals the immune escape and drug resistance mechanisms of mantle cell lymphoma

Objective:Mantle cell lymphoma(MCL)is a rare subtype of non-Hodgkin lymphoma(NHL)with high heterogeneity and a high recurrence rate.How heterogenous cell populations contribute to relapse remains to be elucidated.Methods:We performed single cell RNA sequencing(scRNA-seq)on approximately 4,000 bone marrow cells sampled from one patient with multidrug resistant MCL.We identified 10 subpopulations comprising 4 malignant B cell subtypes,3 T cell subtypes,2 dendritic cell subtypes and 1 natural killer(NK)cell subtype.Subsequently,we identified cell markers,including a series of genes associated with immune escape and drug resistance.In addition,we explored the roles of these genes in the mechanism of immune escape and drug resistance,and we verified the expression imbalance and clinical prognostic potential by using GEO datasets including 211 MCL samples.Results:The major immune escape mechanisms of MCL included anti-perforin activity,decreased immunogenicity and direct inhibition of apoptosis and cell killing,as mediated by type I and II B cells.The drug resistance mechanisms of different cell clusters included drug metabolism,DNA damage repair,apoptosis and survival promotion.Type III B cells closely communicate with other cells.The key genes involved in the resistance mechanisms showed dysregulated expression and may have significant clinical prognostic value.Conclusion:This study investigated potential immune escape and drug resistance mechanisms in MCL.The results may guide individualized treatment and promote the development of therapeutic drugs.

Shuyu pills inhibit immune escape and enhance chemosensitization in hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is characterized by dysregulation of the immune microenvironment and the development of chemoresistance.Specifically,expression of the programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1)axis,an immune checkpoint,may lead to tumour immune escape,resulting in disease progression.The latest research shows that tumour immune escape may be caused by the upregulation of PD-L1 mediated by hypoxia-inducible factor-1 alpha(HIF-1α),and simultaneous inhibition of HIF-1αand PD-L1 has the potential to enhance the host’s antitumour immunity.Moreover,inhibition of the PD-1/PD-L1 axis may mitigate tumour chemoresistance.Shuyu pills(SYPs)contain immunity-enhancing and antitumour components,making them a potential HCC treatment.AIM To investigate the efficacy of SYPs for HCC treatment via simultaneous HIF-1α and PD-L1 inhibition and the mechanism involved.METHODS A subcutaneous xenograft tumour model was first established in BALB/c nude mice by the subcutaneous injection of 1×107 SMMC-7721 cells.Male mice(male,5 weeks old;n=24)were then randomly divided into the following four groups(n=6):Control(0.9%normal saline),SYP(200 mg/kg),SYP+cisplatin(DDP)(200 mg/kg+5 mg/kg DDP weekly via intraperitoneal injection),and DDP(5 mg/kg cisplatin weekly via intraperitoneal injection).The dose of saline or SYPs for the indicated mouse groups was 0.2 mL/d via intragastric administration.The tumour volumes and body weights of the mice were measured every 2 d.The mice were euthanized by cervical dislocation after 14 d of continuous treatment,and the xenograft tissues were excised and weighed.Western blot assays were used to measure the protein expression of HIF-1α,PD1,PD-L1,CD4+T cells,and CD8+T cells in HCC tumours from mice.Quantitative reverse transcription polymerase chain reaction was used for real-time quantitative detection of PD-1,PD-L1,and HIF-1α mRNA expression.An immunofluorescence assay was conducted to examine the expression of CD4+T cells and CD8+T cells.RESULTS Compared to mice in the control group,those in the SYP and SYP+DDP groups exhibited reduced tumour volumes and tumour weights.Moreover,the protein and mRNA expression levels of the oncogene HIF1α and that of the negative immunomodulatory factors PD-1 and PD-L1 were decreased in both the SYP and SYP+DDP groups,with the decrease effects being more prominent in the SYP+DDP group than in the SYP group(HIF-1α protein:Control vs SYP,P=0.0129;control vs SYP+DDP,P=0.0004;control vs DDP,P=0.0152,SYP+DDP vs DDP,P=0.0448;HIF-1αmRNA:control vs SYP,P=0.0009;control vs SYP+DDP,P<0.0001;control vs DDP,P=0.0003,SYP vs SYP+DDP,P=0.0192.PD-1 protein:Control vs SYP,P=0.0099;control vs SYP+DDP,P<0.0001,SPY vs SYP+DDP,P=0.0009;SYP+DDP vs DDP,P<0.0001;PD-1 mRNA:control vs SYP,P=0.0002;control vs SYP+DDP,P<0.0001;control vs DDP,P=0.0003,SPY vs SYP+DDP,P=0.0003;SYP+DDP vs DDP,P=0.0002.PD-L1 protein:control vs SYP,P<0.0001;control vs SYP+DDP,P<0.0001;control vs DDP,P<0.0001,SPY vs SYP+DDP,P=0.0040;SYP+DDP vs DDP,P=0.0010;PD-L1 mRNA:Control vs SYP,P<0.0001;control vs SYP+DDP,P<0.0001;control vs DDP,P<0.0001,SPY vs SYP+DDP,P<0.0001;SYP+DDP vs DDP,P=0.0014).Additionally,the quantitative and protein expression levels of CD4+T cells and CD8+T cells were simultaneously upregulated in the SYP+DDP group,whereas only the expression of CD4+T cells was upregulated in the SYP group.(CD4+T cell quantitative:Control vs SYP+DDP,P<0.0001,SYP vs SYP+DDP,P=0.0005;SYP+DDP vs DDP,P=0.0002.CD4+T cell protein:Control vs SYP,P=0.0033;Control vs SYP+DDP,P<0.0001;Control vs DDP,P=0.0021,SYP vs SYP+DDP,P=0.0004;SYP+DDP vs DDP,P=0.0006.Quantitative CD8+T cells:Control vs SYP+DDP,P=0.0013;SYP vs SYP+DDP,P=0.0347;SYP+DDP vs DDP,P=0.0043.CD8+T cell protein:Control vs SYP+DDP,P<0.0001;SYP vs SYP+DDP,P<0.0001;SYP+DDP vs DDP,P<0.0001).Finally,expression of HIF-1αwas positively correlated with that of PD-1/PD-L1 and negatively correlated with the expression of CD4+T cells and CD8+T cells.CONCLUSION SYPs inhibit immune escape and enhance chemosensitization in HCC via simultaneous inhibition of HIF-1α and PD-L1,thus inhibiting the growth of subcutaneous xenograft HCC tumours.

Morphine-3-glucuronide upregulates PD-L1 expression via TLR4 and promotes the immune escape of non-small cell lung cancer

Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide(M3G)levels.Hence,the effects of M3G on tumor progression are worth studying.Methods:The effects of M3G on PD-L1 expressions in human non-small cell lung cancer(NSCLC)cell lines were first evaluated.Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot.The effects of M3G on human cytotoxic T lymphocytes(CTL)cytotoxicity and INF-γrelease was also detected.Finally,the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model,and the effects of M3G on tumor growth and metastasis were determined.Results:M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner(P<0.05).M3G activated the PI3 K and the NFκB signaling pathways,and this effect was antagonized by a TLR4 pathway inhibitor.A PI3 K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation.M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ.Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment.Conclusions:M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3 K signaling pathway,thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.

Role of cytokines in promoting immune escape of FasL-expressing human colon cancer cells

AIM: To investigate the potential role of cytokines in promoting Fas ligand (FasL)-expressing colon cancer cells. METHODS: Immunohistochemical SABC method was used to observe the expression of Fas receptor and ligand in SW620 colon cancer cell line and Jurkat T cells in order to provide the morphological evidence for the functions of Fas receptor and ligand. To examine the cytotoxicity of effector cells, CytoTox96 non-radioactive cytotoxicity assay was adopted to measure the lactate dehydrogenase-releasing value after SW620 cells were co-cultured with Jurkat T lymphocytes. RESULTS: The FasL of colon cancer SW620 cells was positive. The positive substances were distributed in the cell membrane and cytoplasm. The Fas receptor of colon cancer SW620 cells was negative. The Fas receptor and ligand of Jurkat T lymphocytes turned out to be positive. The positive substances were distributed in the cell membrane. After phytohemagglutinin (PHA)-stimulated Jurkat T lymphocytes were co-cultured with phorbol 12-myristate 13-acetate (PMA)-plus-ionomycin-stimulated (for 48 h) SW620 cells or tumor necrosis factor-alpha (TNF-α)-stimulated (for 48 h) SW620 cells or unstimulated SW620 cells for 4 h, the cytotoxicity of SW620 cells to PHA-stimulated Jurkat cells at effector-to-target ratios of 10:1, 5:1, 2.5:1, and 1.25:1 was 74.6%, 40.8%, 32.4%, and 10.9% (F= 8.19, P<0.05); or 54.9%, 35.3%, 22.0%, and 10.3% (F= 11.12, P<0.05); or 14.9%, 10.5%, 6.9%, and 5.8% (F = 3.45, P<0.05). After PHA-stimulated Jurkat T lymphocytes were co-cultured with unstimulated SW620 cells for 8 h, the cytotoxicity of SW620 cells to PHA-stimulated Jurkat cells at effector-to-target ratios of 5:1, 2.5:1, and 1.25:1 from the experiment was 83.9%, 74.1%, and 28.5% (F=137.04, P<0.05) respectively. Non-radioactive cytotoxicity assay showed that the apoptotic rate of Jurkat cells remarkably increased with the increase of planting concentration of SW620 cells and co-culture time after the SW620 cells were co-cultured with the Jurkat T lymphocytes. The cytotoxicity was significantly enhanced by PMA+ionomycin or TNF-α. CONCLUSION: The FasL expressed in human colon cancer cells may be regulated by endogenous factors in the microenvironment of the host and facilitate the escape of tumor cells from the host immune system.

T cell interactions with microglia in immune-inflammatory processes of ischemic stroke

The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke,which promotes neuronal death and inhibits nerve tissue regeneration.As the first immune cells to be activated after an ischemic stroke,microglia play an important immunomodulatory role in the progression of the condition.After an ischemic stroke,peripheral blood immune cells(mainly T cells)are recruited to the central nervous system by chemokines secreted by immune cells in the brain,where they interact with central nervous system cells(mainly microglia)to trigger a secondary neuroimmune response.This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke.We found that,during ischemic stroke,T cells and microglia demonstrate a more pronounced synergistic effect.Th1,Th17,and M1 microglia can co-secrete proinflammatory factors,such as interferon-γ,tumor necrosis factor-α,and interleukin-1β,to promote neuroinflammation and exacerbate brain injury.Th2,Treg,and M2 microglia jointly secrete anti-inflammatory factors,such as interleukin-4,interleukin-10,and transforming growth factor-β,to inhibit the progression of neuroinflammation,as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury.Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation,which in turn determines the prognosis of ischemic stroke patients.Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke.However,such studies have been relatively infrequent,and clinical experience is still insufficient.In summary,in ischemic stroke,T cell subsets and activated microglia act synergistically to regulate inflammatory progression,mainly by secreting inflammatory factors.In the future,a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells,along with the activation of M2-type microglia.These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

The interaction between end-metabolites and immune escape

Emerging data from metabolites-relating trails in cancers demonstrate that a common mechanism of resistance to many novel classes of immune therapeutics is the emergence of immune escape due to the reprogramming of cellular metabolism.Among them,current work about end-metabolites mostly focuses on the intersection between lactate acid,adenosine,reactive oxygen species(ROS),and tumour immune escape.In this article,we aim to review the evidence to date for the dynamic interplay between the three end-metabolites and tumour immune escape for potential approaches to overcome obstacles in the efficacy and durability of immune cancer therapies.We have organized known end-metabolites-associated immune escape mechanisms into three hallmarks:(1)decreased immunogenicity of cancer cells which constitutes defective antigen presentation and the attenuated expression of costimulatory molecules on tumour cells,(2)immunosuppressive microenvironment with aberrant angiogenesis inhibits the differentiation,maturation,and immune deviation of immune cells while drives the activation of immunosuppressive cells by immune-suppressive mediators(cytokines and other factors),(3)immune tolerance retained by inhibitory molecules and depletion of immune cells.

Advances in research on relationship between tumor immune escape and tumor microenvironment

Tumor immune escape is an important way for tumor cells to evade surveillance and attack by host immune system and promote tumor survival and proliferation.Immunotherapy for immune escape has made significant progress in recent years.Immunotherapy involves multiple factors and pathways,and is associated with changes in tumor cells themselves and tumor microenvironments,and the mechanisms are complex.At present,there are still many challenges in the clinical practice process.Starting from the tumor microenvironment,the article describes the role of various cells in the tumor microenvironment on tumor cell immune escape.

Action and mechanism of Fas and Fas ligand in immune escape of gallbladder carcinoma

AIM: To study the role of Fas and Fas ligand (FasL) in biological behaviors of gallbladder carcinoma, and their correlated action and mechanism in tumor escape.METHODS: Streptavidin-biotin-peroxidase immunohistochemistry technique was used to study the expression of Fas and FasL protein in 26 gallbladder carcinoma tissues,18 gallbladder adenoma tissues, 3 gallbladder dysplasia tissues and 20 chronic cholecystitis tissues. Apoptosis of the infiltrating lymphocytes in these tissues was studied by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Expression of both proteins and apoptosis of the tumor infiltrating lymphocytes in cancer tissues of primary foci was compared with clinicopathological features of gallbladder carcinoma.RESULTS: The positive rates of Fas were not significantly different among carcinoma, adenoma, dysplasia and chronic cholecystitis. The positive rate of FasL in carcinoma was significantly higher than that in chronic cholecystitis (x2 = 4.89, P＜0.05). The apoptotic index (AI) in carcinoma was significantly higher than that in adenoma (t'= 4.19, P＜0.01) and chronic cholecystitis (t'= 8.06, P＜0.01). The AI was significantly lower in well-differentiated carcinoma and Nevin Ⅰ-Ⅲ carcinoma than that in poorly-differentiated carcinoma (t'= 2.63, P＜0.05) and Nevin Ⅳ-Ⅴ carcinoma(t'= 3.33, P＜0.01). The confidence interval (CI) ofinfiltrating lymphocytes in adenoma, chronic cholecystitis, well-differentiated carcinoma and Nevin Ⅰ-Ⅲ carcinoma wasvery significantly lower than that in carcinoma (t' = 6.99,P＜0.01), adenoma (t' = 3.66, P＜0.01), poorly-differentiated carcinoma (t' = 5.31, P＜0.01) and Nevin Ⅳ-Ⅴ carcinoma(t' = 3.76, P＜0.01), respectively. The CI of apoptosis of infiltrating lymphocytes in well-differentiated carcinoma was significantly lower than that in poorly-differentiated carcinoma (t = 2.52, P＜0.05), and was not significantly lower in Nevin Ⅰ-Ⅲ carcinoma than in Nevin Ⅳ-Ⅴ carcinoma (t = 1.42, P＞0.05). Apoptosis of infiltrating lymphocytes was not discovered in adenoma and chronic cholecystitis. CONCLUSION: FasL expressed in gallbladder carcinoma cells permits tumor cells to escape from immune surveillance of organism by inducing apoptosis in infiltrating lymphocytes of carcinoma tissues. Up-regulation of FasL expression plays an important role in invasive depth, histological classification and metastasis of gallbladder carcinoma.

Costimulatory Molecule B7-H1 on the Immune Escape of Bladder Cancer and Its Clinical Significance

B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in tumor immune escape by inducing T-cell apoptosis. In order to investigate the relationship between B7-H1 and immune escape of bladder cancer, B7-H1 expression in 50 cases of bladder cancer was detected by using immunohistochemical method. Survival curves were con- structed using the Kaplan-Meier method and independent prognostic factors were evaluated using the Cox regression model. Our results showed that the positive rate of B7-H1 immunostaining in normal bladder tissue and bladder cancer was 0 and 72% respectively. The expression of B7-H1 was strongly associated with the pathological grade, clinical stage and recurrence （P〈0.05）. The survival rate was significantly lower in patients with B7-H1 positive group than in those with B7-H1 negative group and multi-variable analysis revealed that B7-H1 could be regarded as an independent factor in evaluating the prognosis of bladder cancer. It is concluded that the expression of B7-H1 is strongly associated with neoplastic progression and prognosis of bladder cancer. The manipulation of B7-H1 may become a beneficial target for immunotherapy in human bladder cancer.

Innate and adaptive immune escape mechanisms of hepatitis B virus

Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit and eliminate HBV,viral breakthrough may result due to non-adherence to treatment,the emergence of viral resistance,and a long treatment cycle.Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems.Therefore,understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control.This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.

FasL Expression in Colorectal Carcinoma and Its Significance in Immune Escape of Cancer

To study the significance of FasL expression in immune escape of colorectal carcinoma, FasL protein expression and the number of tumor infiltrating lymphocytes （TILs） in 80 specimens of colorectal carcinoma were detected by immunohistochemitry. The mRNA of FasL was measured by in situ hybridization in the consecutive tissue slices of 80 colorectal carcinomas respectively. Using terminal deoxynucleotidyl transferase-mediaed dUTP nick end labeling （TUNEL）, apoptotic cells were detected in 80 specimens of colorectal carcinoma. The expression of FasL was detected in all 80 specimens, but it was not even in the same or among different tissues. In the consecutive tissue slices, the location of expression of FasL protein corresponded with that of FasL mRNA. In those with FasL extensive expression, the number of TILs was less than that of FasL weak expression （P〈0. 05）, and the apoptotic index （AI） of TILs was higher and that of tumor cells was lower than that of FasL with weak expression respectively （P〈0. 01）. The AI of TILs was correlated with that of tumor cells （r=-0. 631, P〈0. 01）. It was suggested that colorectal carcinoma cells can induce the apoptosis of TILs through the expression of FasL, which can counterattack the immune system. This may be one of the mechanisms of immune evasion in colorectal carcinoma.

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Heat shock proteins (HSPs) serve to correct proteins’ conformation, send the damaged proteins for degradation (quality control function). Heat shock factors (HSFs) are their transcription factors. The protein complexes mTOR1 and 2 (with the same core mTOR), the phosphoinositide-dependent protein kinase-1 (PDK1), the seine/threonine-specific protein kinase (Akt), HSF1, plus their associated proteins form a network participating in protein synthesis, bio-energy generation, signaling for apoptosis with the help of HSPs. A cancer cell synthesizes proteins at fast rate and needs more HSPs to work on quality control. Shutting down this network would lead to cell death. Thus inhibitors of mTOR (mTORI) and inhibitors of HSPs (HSPI) could drive cancer cell to apoptosis—a “passive approach”. On the other hand, HSPs form complexes with polypeptides characteristic of the cancer cells;on excretion from the cell, they becomes antigens for the immunity cells, eventually leading to maturation of the cytotoxic T cells, forming the basic principle of preparing cancer-specific, person-specific vaccine. Recent finding shows that HSP70 can penetrate cancer cell and expel its analog to extracellular region, giving the hope to prepare a non-person-specific vaccine covering a variety of cancers. Activation of anti-cancer immunity is the “active approach”. On the other hand, mild hyperthermia, with increase of intracellular HSPs, has been found to activate the immunity response, and demonstrate anti-cancer effects. There are certain “mysteries” behind the mechanisms of the active and passive approaches. We analyze the mechanisms involved and provide explanations to some mysteries. We also suggest future research to improve our understanding of these two approaches, in which HSPs play many roles.

Modulation of postoperative immune and inflammatory response by immune-enhancing enteral diet in gastrointestinal cancer patients

AIM: To evaluate if the administration of an enteral diet supplemented with glutamine, arginine and omega-3-fatty acids modulates inflammatory and immune responses after surgery. METHODS: A prospective randomized double-blind, clinical trial was performed. Forty-eight patients with gastrointestinal cancer were randomized into two groups, one group was given an isocaloric and isonitrogenous standard diet and the other was fed with the supplemented diet with glutamine, arginine and omega-3-fatty acids. Feedings were started within 48 hours after operation, and continued until day 8. All variables were measured before operation and on postoperative day 1 and 8. Immune responses were determined by phagocytosis ability, respiratory burst of polymorphonuclear cells, total lymphocytes lymphocyte subsets, nitric oxide, cytokines concentration, and inflammatory responses by plasma levels of C-reactive protein, prostaglandin E2 level. RESULTS: Tolerance of both formula diets was excellent.There were significant differences in the immunological and inflammatory responses between the two groups. In supplemented group, phagocytosis and respiratory burst after surgery was higher and C-reactive protein level was lower (P【0.01) than in the standard group. The supplemented group had higher levels of nitric oxide, total lymphocytes, T lymphocytes, T-helper cells, and NK cells. Postoperative levels of IL-6 and TNF-alpha were lower in the supplemented group (P 【0.05). CONCLUSION: It was clearly established in this trial that early postoperative enteral feeding is safe in patients who have undergone major operations for gastrointestinal cancer. Supplementation of enteral nutrition with glutamine, arginine, and omega-3-fatty acids positively modulated postsurgical immunosuppressive and inflammatory responses.

Viro-immune therapy:A new strategy for treatment ofpancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.

Prevention of Hearing Loss by Alteration of the Systemic Immune System

Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, including autoimmunity, chronic inflammation, and immunosenescence. We have investigated the relationship between the inner ear and systemic immunity and reviewed the possibilities to prevent SHL, including autoimmune SHL and age-related SHL. We also demonstrated two lymphocyte populations, interleukin 1 receptor type II (IL-1R2)-positive T cells (T1R2) and naturally occurring regulatory T cells (nTregs) in CD4+ T cells, which increase with aging, suppress host immune function and promote organ degeneration. Alterations in systemic immunity by fewer microbial antigen challenges in the living environment, elimination of immune suppressive lymphocytes, or immune rejuvenation with a reconstituted thymus may contribute not only to renew the cochlear function in SHL, but also to extend the healthy life of functional organs in a vigorous and youthful body, one of humanity’s greatest dreams.

Role of T cell death in maintaining immune tolerance during persistent viral hepatitis

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate na ve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.