Gut bacteria affect the tumoral immune milieu: distorting the efficacy of immunotherapy or not？

ABSTRACT

Immunotherapy using immune-checkpoint inhibitors is revolutionizing oncotherapy. However, the application of immunotherapy may be restricted because of the lack of proper biomarkers in a portion of cancer patients. Recently, emerging evidence has revealed that gut commensal bacteria can impact the therapeutic efficacy of immune-checkpoint inhibitors in several cancer models. In addition, testing the composition of gut bacteria provides context for prediction of the efficacy and toxicity of immunotherapy. In this review, we discuss the impacts of gut commensal bacteria on the tumoral immune milieu, highlighting some typical bacteria and their associations with immunotherapy.     

基因芯片技术在胰腺癌中的应用进展

基因芯片技术是近几年发展起来的一项生物技术,可同时对大量基因的表达、突变和多态性进行快速、准确的检测。基因芯片技术为研究肿瘤发生、发展中基因功能分析,提供了强有力的工具。胰腺癌在我国的发病率逐年增长,利用基因芯片技术,为胰腺癌的分子病理诊断、临床预后判断及治疗方案的选择提供理论指导。这必将加速对胰腺癌发生、发展机制的了解,为进一步诊断和治疗提供理论基础。     

Alcohol Ingestion Impairs Host Defenses Predisposing Otherwise Healthy Mice to Pneumocystis carinii Infection

Pulmonary infection with Pneumocystis carinii, an opportunistic pathogen, is associated with a variety of immunosuppressive states, Including human immunodeficiency virus infection. We hypothesized that alcohol ingestion might compromise host defenses against this pathogen and, in an immunocompromised host, increase the severity of infection. This hypothesis was tested in both acute and chronic ethanol-treated normal and CD4⁺ T-cell-depleted mice challenged with P. carinii organisms. Normal and CD4⁺ T-cell-depleted mice were given an intraperitoneal injection of ethanol or saline 0.5 hr before P. carinii challenge and killed 3 hr later for bronchoalveolar lavage. Acute alcohol treatment decreased significantly tumor necrosis factor (TNF) activity and the number of polymorphonuclear leukocytes (PMNLs) recovered in the lavage in response to the pathogen. Depletion of CD4⁺ T-cells did not potentiate the effect of alcohol on the early inflammatory response to the pathogen any further. In normal animals, in vivo interferon (IFN)-γ pretreatment augmented significantly the P. carinii- stimulated lung TNF response and PMNL recruitment. However, IFN-γ pretreatment prevented the alcohol-induced suppression of TNF secretion without affecting the PMNL recruitment. The effect of chronic alcohol consumption on the severity of infection was studied in long-term, alcohol-fed normal and CD4⁺-depleted mice challenged with P. carinii organisms. Lung histopathology showed that P. carinii infection was present in >60% of the alcohol-fed mice and in none of the controls. Also, a significantly higher number of PMNLs were recovered in the lavage fluid of alcohol-fed mice with persistent infection. There was no difference in lavage fluid and cell culture supernatant TNF and reactive nitrogen intermediates release between the two groups. CD4⁺ T-cell depletion did not alter significantly the effect of alcohol on any of the aforementioned parameters. We conclude that chronic alcohol ingestion alone induces immunosuppression sufficient to permit pulmonary infection with P. carinii. One possible mechanism for the adverse effects of alcohol on host defenses against P. carinii may be through suppressed host release of cytokines including TNF-α and IFN-γ.     

Autologous T lymphocytes recognize the tumour-derived immunoglobulin VH-CDR3 region in patients with B-cell chronic lymphocytic leukaemia

We have previously shown that autologous T cells recognize leukaemic cells from patients with chronic lymphocytic leukaemia (B-CLL) in an MHC class I- and/or II-restricted manner. A candidate recognition structure might be the tumour cell-derived Ig VH complementarity-determining region (CDR)3. Three patients with B-CLL were analysed for the presence of autologous T cells recognizing the tumour-specific VH-CDR3 region. The VH region was shown to be mutated in all three patients. In two patients, a VH-CDR3-specific T-cell response was detected by proliferation assay, as well as by gamma-interferon (IFN) production. The responses could be inhibited by monoclonal antibodies against MHC class II, but not MHC class I. In the third patient, a VH-CDR3 proliferative response was detected, which could be inhibited by an anti-MHC class I monoclonal antibody, but not by anti-MHC class II antibodies. No gamma-IFN response could be detected in this patient. In no patient was an interleukin (IL)-4 response noted. Thus, in patients with B-CLL, naturally occurring T cells recognizing the tumour-unique VH-CDR3 region are present.     

HBeAg阴、阳性慢乙肝患者细胞免疫状态及HBVDNA水平分析

目的 对比HBeAg阴性及HBeAg阳性慢性乙肝患者在细胞免疫状态及HBV DNA水平方面的差别,分析造成这种差别的可能原因.方法 应用流式细胞仪进行T淋巴细胞分类检测、荧光定量PCR测量血清中的HBVDNA.结果 在HBVDNA水平方面,HBeAg阴性慢性乙肝患者均值为(5.13±1.43)Log,显著低于HBeAg阳性组的(6.29±1.70)Log(P＜0.05);在T淋巴细胞分类方面,HBeAg阴性慢性乙肝患者CD8 T显著高于HBeAg阳性患者,分别是:23.25±3.79和20.69±3.30(P＜0.05),总T、CD4 T及CD8 /CD8 比值方面两组无明显差别(P＞0.05).结论 HBeAg阴性慢性乙肝患者HBV DNA水平低于HBeAg阳性患者,可能与HBeAg阴性慢性乙肝患者具有相对较强的细胞免疫状态有关.     

The search for an influence of whole-body microwave hyperthermia on anti-tumor immunity

Summary The effect of microwave whole-body hyperthermia was examined on the takes of tumor after i.v. administration of the tumor single cell suspension. It was shown that the longer the exposure to hyperthermia treatment the higher the number of lung nodules obtained by injection of the same dose of tumor cells. Also, the expression of contact hypersensitivity to oxazolone was strongly inhibited after hyperthermia treatment. It was documented that it is possible to transfer the diminished resistance to tumor with bone marrow, whereas impaired responsiveness to oxazolone was transferred with spleen cells or thymocytes.This work was supported by Research Grant PR-6-210-02 from the Polish Governmental Program     

Importance of CD4<Superscript>+</Superscript> Helper T-cells in Antitumor Immunity

CD8+ cytotoxic T-lymphocytes are major effector cells involved in immunologically specific tumor destruction in vivo, and CD4+ T-cells are essential for controlling this CD8+ T-cell-dependent tumor eradication. The presence of CD4+ T-cells with distinct functional roles has been recognized. The further understanding of the complexity of antitumor immune responses by CD4+ T-cells may be crucial for designing more effective cancer vaccines.     

活血化瘀注射液Ⅰ号预处理与缺血预处理改善肝缺血再灌注损伤

目的:研究活血化瘀注射液Ⅰ号(HHI-Ⅰ)预处理与缺血预处理(ischemic preconditioning,IP)对大鼠肝脏缺血再灌注(ischemia and reperfusion,I/R)损伤的改善作用,并比较两者的作用效果.方法:健康♂SD大鼠80只,随机分为假手术对照组(Sham组)、缺血再灌注组(I/R组)、缺血预处理组(IP组)、HHI-Ⅰ预处理组(HHI-Ⅰ组),每组20只.建立大鼠部分肝缺血模型,各组在I/R后1,3,6,24 h分别取材,测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、乳酸脱氢酶(LDH)的水平;取左肝测组织丙二醛(MDA)、超氧化物歧化酶(SOD)的含量.I/R后1 h RTPCR检测肝组织中肿瘤坏死因子α(TNF-α)和细胞间黏附分子-1(ICAM-1)mRNA的表达,I/R后3 h行组织学观察.结果:I/R组、IP组、HHI-Ⅰ组的ALT,AST,LDH活性、MDA值和TNF-α,ICAM-1 mRNA表达水平均明显高于Sham组.IP组、HHI-Ⅰ组低于I/R组.HHI-Ⅰ组所有时间点ALT,AST,LDH明显低于IP组(ALT:2378.8±303.4 nkat/Lvs 2840.6±248.4 nkat/L;AST:2887.2±270.1nkat/L vs 4567.6±275.1 nkat/L;LDH:10550.4±710.1 nkat/L vs 12164.1±735.1 nkat/L;P均＜0.05).HHI-I组MDA值明显低于IP组(17.35±1.39 nmol/g vs 21.66±1.84 nmol/g,P＜0.05).HHI-Ⅰ组TNF-α,ICAM-1 mRNA表达水平低于IP组(TNF-α:0.54±0.06 vs 0.78±0.08;ICAM-1:0.43±0.03 vs 0.69±0.11,P均＜0.01).各组SOD值均低于Sham组(P＜0.05),IP组、HHI-Ⅰ组均高于I/R组(P＜0.05),HHI-Ⅰ组SOD(1,3,6 h)明显高于IP组(136.00±12.50 nmol/g vs 124.70±9.32 nmol/g,P＜0.05).Sham组光镜下肝小叶结构正常;I/R组肝小叶结构紊乱,肝细胞水肿变性;IP组肝细胞水肿明显,部分肝细胞变性;HHI-Ⅰ组肝小叶结构基本正常,肝细胞无明显水肿.结论:HHI-Ⅰ预处理与IP均可改善I/R对肝脏造成的损伤,前者的效果优于后者.HHI-Ⅰ的保护机制可能在于改善肝脏微循环,减轻组织缺氧状态,并通过抑制TNF-α和ICAM-1等细胞因子和细胞黏附分子的转录表达,减少肝组织中中性粒细胞的浸润.     

Does hyaluronan affect inflammatory cytokines in knee osteoarthritis?

Our aim was to investigate the effects of hyaluronan on inflammatory cytokines in the synovial fluid of patients with knee osteoarthritis. The study was single blind, placebo-controlled, and randomized. We administered hyaluronan to 22 patients in the study group and placebo to 19 in the control group. Enzyme-linked immunosorbent assay was used to determine the levels of cytokines. Both HA and placebo caused a significant decrease in interleukin (IL)-6 levels (P=0.0001 and P=0.04, respectively). But it was more significant in the study group. However, IL-8 and tumor necrosis factor alpha (TNF-) levels did not change in either group (P>0.05). The amount of effusion decreased significantly in the study group (P=0.001) but not in the control group (P=0.133). It can be concluded that hyaluronan considerably decreased IL-6 levels, which correlated with clinical improvement, but had no effect on IL-8 and TNF- levels in synovial fluid. However, larger studies with longer follow-up periods are needed to explain the effect of hyaluronan on cytokines.     

Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3

AIM: To investigate the association between cytokine gene polymorphism and disease status in chronic hepatitis C genotype 3 by liver biopsy, ALT, HCV RNA levels and response to treatment. METHODS: Patients with chronic hepatitis C genotype 3 were analyzed for single nucleotide polymorphisms of interleukin (IL)-10, IL-1 beta, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) by polymerase chain reaction using sequence-specific oligonucleotide primers. Liver biopsies were assessed by modified histological activity index (HAI) scoring system using a scale of 0-18 for grading the necro-inflammatory activity and 0-6 for staging the fibrosis. HCV RNA levels were determined by bDNA assay. The patients were treated with interferon alpha and ribavirin for 6 mo. Sustained virological response was assessed 6 mo after the completion of the treatment. RESULTS: Out of the 40 patients analyzed, 26 were males. Mean age was 40.5±12.5 years (range 18-65 years). The frequencies of different dimorphic polymorphisms based on single nucleotide substitution were as follows: IL-10-1082 G/A 85%, A/A 12.5%, G/ G 2.5%; IL-10-819 A/C 87.5%, C/C 10%, A/A 2.5%; IL-10-592 C/A 72.5%, C/C 27.5%; IL-1 C 90%, U 10%; IFN-874 T/A 50%, T/T 27.5%, A/A 22.5%; TNF-308 A/G 95%, GIG 5%; TGF-10 T/C 52.5%, C/C 35%, T/T 12.5%. The mean grades of necro-inflammatory activity of different genotypes of IL-10 at promoter site -1082 were A/A = 3.6, A/G = 5.0, and G/G = 10.0 and the difference was significant (P = 0.029). The difference in the stage of disease at a scale of 0-6 was A/A 0.8, A/G 2.3, and G/G 4.0 (P = 0.079). The difference in the HAI seemed to be related to the presence of allele -1082G. For IL-10 -819 genotypes, mean scores of fibrosis were A/A = 6.0, A/C = 2.2, and C/C = 1.0 (P = 0.020) though the inflammatory activity was not much different. No significant differences in HAI were noted among polymorphisms of other cytokines. Moreover, ALT and HCV RNA levels were not significantly different among different cvtokine polymorphisms. There was a significant correlation of HAI and HCV RNA levels with the duration of disease. TGFBBB -10 genotype CC patients had a better end of treatment response than those with other genotypes (P = 0.020). Sustained virological response to the treatment was not influenced by the cytokine polymorphism. No effect of other factors like viral load, degree of fibrosis, gender, steatosis, was observed on sustained virological response in this population infected with genotype 3. CONCLUSION: There is no significant correlation between cytokine polymorphisms and HAI except for the polymorphisms of anti-inflammatory cytokine IL-10, which may influence hepatic inflammatory activity and fibrosis in patients with chronic hepatitis C genotype 3. Sustained virological response in this genotype does not seem to be influenced by cytokine gene polymorphisms.