Indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 expression prediction for adverse prognosis in colorectal cancer

AIM To evaluate indoleamine-2,3-dioxygenase 1/cyclooxygenase 2(IDO1/COX2) expression as an independent prognostic biomarker for colorectal cancer(CRC) patients.METHODS We retrospectively studied the medical records of 95 patients who received surgical resection from August 2008 to January 2010. All patients were randomly assigned to adjuvant treatment with or without celecoxib groups after surgery. We performed standard immunohistochemistry to assess the expression levels of IDO1/COX2 and evaluated the correlation of IDO1/COX2 with clinicopathological factors and overall survival(OS) outcomes.RESULTS The expression of nuclear IDO1 was significantly correlated with body mass index(P < 0.001), and IDO1 expression displayed no association with sex, age, tumor differentiation, T stage, N stage, carcinoembryonic antigen, cancer antigen 19-9, CD3+ and CD8+ tumor infiltrating lymphocytes, and COX2. In univariate analysis, we found that nuclear IDO1(P = 0.039), nuclear/cytoplasmic IDO1 [hazard ratio(HR) = 2.044, 95% confidence interval(CI): 0.871-4.798, P = 0.039], nuclear IDO1/COX2(HR = 3.048, 95%CI: 0.868-10.7, P = 0.0049) and cytoplasmic IDO1/COX2(HR = 2.109, 95%CI: 0.976-4.558, P = 0.022) all yielded significantly poor OS outcomes. Nuclear IDO1(P = 0.041), nuclear/cytoplasmic IDO1(HR = 3.023, 95%CI: 0.585-15.61, P = 0.041) and cytoplasmic IDO1/COX2(HR = 2.740, 95%CI: 0.764-9.831, P = 0.038) have significantly poor OS outcomes for the CRC celecoxib subgroup. In our multivariate Cox model, high coexpression of cytoplasmic IDO1/COX2 was found to be an independent predictor of poor outcome in CRC(HR = 2.218, 95%CI: 1.011-4.48, P = 0.047) and celecoxib subgroup patients(HR = 3.210, 95%CI: 1.074-9.590, P = 0.037).CONCLUSION Our results showed that cytoplasmic IDO1/COX2 coexpression could be used as an independent poor predictor for OS in CRC.

Feiji Recipe inhibits the growth of lung cancer by modulating T-cell immunity through indoleamine-2,3-dioxygenase pathway in an orthotopic implantation model

Objective： Escape from the body＇s immune response is a basic characteristic of lung cancer, and indoleamine-2,3-dioxygenase （IDO） plays a key role in mediating immune escape of non-small-cell lung cancer, which leads to recurrence and metastasis. Feiji Recipe, a compound Chinese herbal medicine, has the effect of stabilizing lesions and prolonging survival in patients with lung cancer. The purpose of this study was to investigate the mechanisms underlying the anticancer properties of Feiji Recipe. Methods： An orthotopic transplant model of mouse Lewis lung cancer, with stable expression of IDO gene, was established in C57BL/6 mice. Optical imaging was used to observe the effects of Feiji Recipe in the treatment of lung cancer in vivo. The effects of Feiji Recipe on the proliferation of mouse Lewis lung cancer cell line 2LL, 2LL-enhanced green fluorescent protein （2LL-EGFP） and 2LL-EGFP-IDO were investi- gated, and the apoptosis of T-cells was examined by 3-（4,5-dimethyl-2-thiazolyl）-2,5-diphenyl-2H-tetra zolium bromide using flow cytometry. Chemical composition of Feiji Recipe was validated by high- performance liquid chromatography. Results： Compared to the control group, the survival of animals treated with Feiji Recipe was significantly prolonged （P〈0.0074）, and the IDO protein level decreased （P=0.0072）; moreover, the percentages of CD4＋CD25＋ T-cells and Foxp3＋ T-cells were significantly decreased （P〈0.05）. The molecular mechanism of Feiji Recipe against lung cancer may relate to the regulation of immune cells, such as T-cells and reg- ulatory T-cells. Conclusion： The molecular mechanism of Feiji Recipe in treatment of lung cancer is to restore the function of T-cells in the cancer microenvironment through interfering with the IDO pathway.

Recombinant adenovirus with human indoleamine-2,3- dioxygenase and hepatitis B virus preS was constructed and expressed in HepG2 cells

Background Indoleamine-2,3-dioxygenase （IDO） is proven to suppress hepatitis B virus （HBV） specific immune response and depletion of IDO may be a useful approach for HBV therapy. To test this concept, we constructed recombinant adenovirus with human IDO and HBV preS, which would form the basis for future in vivo experiments.Methods The fragment of human IDO and HBV preS cDNA were subcloned into multiple cloning sites in an adenoviral vector system containing two cytomegalovirus （CMV） promoters. Recombination was conducted in the Escherichia coli BJ5183. The recombinant adenovirus containing hlDO gene and HBVpreS gene was packaged and amplified in 293 cells.Integration was confirmed by polymerase chain reaction as well as the quantification of viral titers. HepG2 cells were infected with the recombinant adenovirus and mRNA and protein specific for hlDO and HBVpreS was detected by RT-PCR and Western blotting respectively.Results The recombinant adenovirus was produced successfully. Its titer was 2.5x109 efu/ml. IDO and HBVpreS mRNA as well as the encoded proteins could be found in transfected HepG2 cells, but not in control HepG2 cells.Conclusion The transfer of hlDO-HBVpreS with double-promoter adenoviral vector was efficient. The recombinant adenovirus with hlDO and HBVpreS would provide the experimental basis for future studies.

天丝饮的抗抑郁作用及其对IDO的调节

目的研究天丝饮的抗抑郁作用及其对色氨酸(TRP)、犬尿氨酸(KYN)途径关键代谢酶吲哚胺2,3过氧化酶(IDO)的影响。方法使用脂多糖(LPS)腹腔注射1 mg/kg造成小鼠抑郁模型,采用Noldus Etho Vision XT9系统采集分析小鼠强迫游泳不动时间,采用HPLC-MS/MS技术检测脑组织色氨酸、犬尿氨酸含量,实时荧光定量PCR检测脑组织中IDO、NF-κB的mRNA表达水平。结果 LPS注射4 h后可以引起模型组小鼠不动时间延长(P<0.05),脑组织IDO活性增高,IDO和NF-κB mRNA表达增多(P<0.01)。天丝饮能缩短小鼠不动时间(P<0.05),抑制IDO活性及IDO、NF-KB mRNA表达数量(P<0.01)。结论天丝饮具有抗抑郁药物样作用,这一作用与抑制炎症因子诱导的IDO激活有关,天丝饮通过抑制NF-κB对IDO的直接和间接诱导作用而调节了IDO的活性和表达。

Immunogenic-cell-killing and immunosuppression-inhibiting nanomedicine

Combining chemo-therapeutics with immune checkpoint inhibitors facilitates killing cancer cells and activating the immune system through inhibiting immune escape.However,their treatment effects remain limited due to the compromised accumulation of both drugs and inhibitors in certain tumor tissues.Herein,a new poly(acrylamide-co-acrylonitrile-co-vinylimidazole-co-bis(2-methacryloyl)oxyethyl disulfide)(PAAVB)polymer-based intelligent platform with controllable upper critical solution temperature(UCST)was used for the simultaneous delivery of paclitaxel(PTX)and curcumin(CUR).Additionally,a hyaluronic acid(HA)layer was coated on the surface of PAAVB NPs to target the CD44-overexpressed tumor cells.The proposed nanomedicine demonstrated a gratifying accumulation in tumor tissue and uptake by cancer cells.Then,the acidic microenvironment and high level of glutathione(GSH)in cancer cells could spontaneously decrease the UCST of polymer,leading to the disassembly of the NPs and rapid drug release at body temperature without extra-stimuli.Significantly,the released PTX and CUR could induce the immunogenic cell death(ICD)to promote adaptive anti-tumor immunogenicity and inhibit immunosuppression through suppressing the activity of indoleamine 2,3-dioxygenase 1(IDO1)enzyme respectively.Therefore,the synergism of this intelligent nanomedicine can suppress primary breast tumor growth and inhibit their lung metastasis.