Study of indoleamine 2,3-dioxygenase expression in patients with breast cancer

We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) in breast cancer. Operative specimens obtained from 30 patients with breast cancer were investigated by semiquantitative RT-PCR with specific primers against IDO. The correlations among IDO expression, clinicopathologic factors and prognosis were studied. The expression of IDO was observed in 100%, both of the cancer specimens and the non-cancer specimens. The IDO expression of the cancer specimens was higher than the non-cancer specimens. The expression of IDO did not correlate to histologic classification, tumor size, lymphatic invasion, venous invasion and lymph nodes metastasis, but correlated to clinical stage and the serum level of immunosuppressive acidic protein (IAP). There were no correlations for a survival rate after surgery between the high IDO level group and the one. The serum IDO levels of cancer patients were higher than that of a healthy volunteer measured by semiquantitative RT-PCR and HPLC. It is suggested that the expression of IDO in breast cancer patients may play a critical role for immunosuppression in those patients.     

High expression of indoleamine 2,3-dioxygenase gene in prostate cancer

Arginase 2, inducible- and endothelial-nitric-oxide synthase (iNOS and eNOS), indoleamine 2,3-dioxygenase (IDO) and TGF-beta, might impair immune functions in prostate cancer (PCA) patients. However, their expression was not comparatively analysed in PCA and benign prostatic hyperplasia (BPH). We evaluated the expression of these genes in PCA and BPH tissues. Seventy-six patients (42 BPH, 34 PCA) were enrolled. Arginase 2, eNOS and iNOS gene expression was similar in BPH and PCA tissues. TGF-beta1 gene expression was higher in BPH than in PCA tissues (p=0.035). IDO gene expression was more frequently detectable (p=0.00007) and quantitatively higher (p=0.00001) in PCA tissues than in BPH. IDO protein, expressed in endothelial cells from both BPH and PCA, was detectable in tumour cells in PCA showing evidence of high specific gene expression. In these patients, IDO gene expression correlated with kynurenine/tryptophan ratio in sera. Thus high expression of IDO gene is specifically detectable in PCA.     

Study of indoleamine 2,3-dioxygenase expression in patients of thyroid cancer

We evaluated a clinical significance of indoleamine 2,3-dioxygenase (IDO) in thyroid cancers. Operative specimens obtained from 20 patients with thyroid cancers were investigated by semi-quantitative RT-PCR with specific primers against IDO. The correlations among IDO expression, clinicopathologic factors and prognosis were studied. An expression of IDO was observed in 100% for both of the cancer specimens and the non-cancer specimens. The IDO expression of cancer specimens was significantly higher than the non-cancer specimens. The expression of IDO did not correlate to histologic classification, tumor size, lymphatic invasion, venous invasion and lymph nodes metastasis, but it was correlated to clinical stage. There was no correlation for survival rate after surgery between the high IDO level group and low IDO level group. The serum IDO levels of cancer patients were higher than that of a healthy volunteer measured by semi-quantitative RT- PCR and HPLC. It is suggested that the expression of IDO in thyroid cancer patients may play critical role for immunosuppression of those patients.     

Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer

Background:

Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolising enzyme that induces immune tolerance by modulating T-cell responses. Carcinomas may create an immunosuppressive state via IDO1 expression. Here we examined a possible contribution of IDO1 on this phenomenon and investigated whether IDO1 has prognostic value in colorectal cancer (CRC).

Methods:

IDO1 expression was investigated by quantitative PCR and western blotting in three colon cancer cell lines, in basal state and after interferon (IFN)-γ stimulation. Semi-quantitative immunohistochemistry was used to evaluate IDO1 expression in 265 pT1-4N0-2Mx-staged CRCs. Results were related to clinical variables and correlated with amounts of CD3⁺ and CD8⁺ T lymphocytes, which were quantitatively evaluated using image analysis.

Results:

In vitro expression of IDO1 depended on IFN-γ stimulation. Higher IDO1 expression at the tumour invasion front was an independent adverse prognostic factor in pT1-4N1Mx-staged CRC. It was associated with overall survival (P=0.001) and with metachronous metastases (P=0.018). IDO1 expression was not associated with the presence of CD3⁺ or CD8⁺ T lymphocytes.

Conclusion:

Higher IDO1 expression at the tumour invasion front is involved in CRC progression and correlates with impaired clinical outcome, suggesting that IDO1 is an independent prognostic indicator for CRC.     

Chemoresistance was correlated with elevated expression and activity of indoleamine 2,3-dioxygenase in breast cancer

Cancer Chemotherapy and Pharmacology - Indoleamine 2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan leading to the production of immunosuppressive kynurenine and...     

吲哚胺2,3双加氧酶在乳腺癌中的表达及其与预后的关系

目的 探讨吲哚胺2,3双加氧酶(IDO)在乳腺癌中的表达及其与乳腺癌临床病理特征、预后的关系.方法 收集40例乳腺癌蜡块,应用免疫组化SP法检测乳腺癌组织中IDO的表达,并对全部标本用CD31和CD105对肿瘤血管内皮细胞进行染色,计数肿瘤微血管密度(MVD),结合患者的临床病理特征及预后进行分析.结果 乳腺癌组织中IDO蛋白高表达率为67.5%(27/40),其表达与临床分期和淋巴结转移相关(均P＜0.05).IDO高表达组与低表达组的3年、 5年无瘤生存率差异均无统计学意义(P=0.211,P=0.523).乳腺癌组织中IDO表达与CD105标记的MVD值呈正相关(r=0.659,P＜0.05),与CD31标记的MVD值无关.结论 IDO可能通过促进新生血管形成加速乳腺癌的进展和转移,IDO表达与乳腺癌患者预后的关系需要进一步扩大样本量加以明确.

Abstract：

Objective To investigate the expression of indoleamine 2,3-dioxygenase (IDO) in breast cancer and its correlation with clinicopathologic factors and prognosis. Methods The expression of IDO, CD31, CD105 proteins in 40 specimens of breast cancer were assessed by immunohistochemistry. Results The overexpression rate of IDO in breast cancer was 67.5% (27/40), and expression of IDO was closely associated with clinical stage and lymph nodes metastasis. The disease-free survival rate in patients with IDO overexpression was not significantly lower than that in patients with negative or low expression of IDO(P>0.05). Moreover, the expression of IDO was positively correlated with CD105-labeled microvessel density (r=0.659,P<0.05). Conclusions Expression of IDO is associated with clinical stage and lymph nodes metastasis, and microvessel densitty. IDO expression may promote the growth and metastasis of breast cancer, probably via the increased agiogenesis. A larger sample study is needed to verify whether the prognosis of beast cancer is significantly correlated with IDO expression.     

吲哚胺2,3-双加氧酶在肝癌组织的表达及其临床意义

目的：探讨吲哚胺2，3-双加氧酶（indoleamine 2，3-dioxygenase，IDO）在原发性肝癌细胞、癌旁肝细胞及肿瘤浸润淋巴细胞中的表达及其临床意义。方法：选择经临床确诊的21例原发性肝癌患者的手术切除和（或）肝穿刺所取肝癌组织及癌旁组织标本，通过免疫组织化学染色法检测肝癌及癌旁组织IDO的表达，并分析其与临床病理特征的关系。结果：IDO在原发性肝癌细胞与肿瘤浸润淋巴细胞的表达水平相对较低，在癌旁肝硬变细胞中表达明显增高（P〈0．01）。IDO表达强度与患者的年龄、性别、TNM分期无关（P〉0．05）；与患者大体病理分型有一定的相关性，浸润型IDO表达强度较块状型明显增高（P〈0．05）；有血管浸润及癌栓形成患者IDO也呈高表达状态（P〈0．05）；IDO的表达还与病理组织学分化情况相关，低分化肿瘤组织IDO的表达强度明显增高（P〈0．05）。结论：IDO的表达与肝细胞癌恶性有一定的相关，故IDO拟可以作肝癌预后差的一个参考指标。     

乳腺癌患者IDO表达及活性与新辅助化疗疗效的相关性研究

  目的  分析吲哚胺2,3-双加氧酶（indoleamine 2,3-dioxygenase,IDO）在乳腺癌患者癌组织中表达及其在外周血中活性与新辅助化疗疗效的关系。  方法  收集2015年9月至2016年12月天津医科大学肿瘤医院53例行新辅助化疗乳腺癌患者的肿瘤穿刺标本和血液标本,采用免疫组织化学法及高效液相色谱法检测癌组织中IDO表达及外周血中色氨酸（tryptophan,Trp）、犬尿氨酸（kynurenine,Kyn）浓度与IDO活性,分析IDO表达及活性与化疗疗效的相关性。  结果  新辅助化疗前乳腺癌组织中IDO表达与临床T分期（P=0.006）、N分期（P=0.020）、临床分期（P=0.045）及ER状态（P=0.014）有关。新辅助化疗前外周血中IDO高活性伴随癌组织中IDO高表达（P=0.004）,并与临床T分期（P=0.019）及N分期（P=0.047）有关。单因素分析显示新辅助化疗临床疗效与化疗前临床T分期（P=0.049）、ER状态（P=0.025）及分子分型（P=0.014）有关;病理完全缓解（pathologic complete response,pCR）与化疗前临床T分期（P=0.014）有关。更重要的是新辅助化疗临床疗效及pCR均与化疗前IDO表达及活性有关（均P < 0.05）。多因素分析显示新辅助化疗前外周血中IDO活性是影响pCR的唯一独立因素（P=0.032）。  结论  新辅助化疗前乳腺癌组织中IDO表达和外周血中IDO活性与化疗疗效相关,可以为临床预测化疗是否敏感提供一定信息。      

IDO在食管癌组织及血清中的表达及对进展的预测价值

目的:通过观察吲哚胺2,3－双加氧酶（IDO）在肿瘤及血清中的表达,探讨其是否可以作为评价食管癌进展情况的预测指标。方法:选取本院2015年01月至2017年12月行食管癌根治术的患者88例,根据是否存在淋巴浸润分成2组,其中淋巴浸润包含淋巴管侵犯和淋巴结转移,另外选取20名健康志愿者作为对照组,采用免疫组化半定量法检测IDO在食管癌及癌旁组织中的表达,高效液相色谱法检测Trp和Kyn在血清中的浓度,计算Kyn/Trp值,最后比较与健康志愿者的差异及与患者临床病理因素的关系。结果:88例患者中有46例存在淋巴浸润,其中24例患者有淋巴结转移;22例患者无淋巴结转移。淋巴管侵犯阳性组患者的IDO阳性表达水平（42.78±6.43）%显著高于阴性组(21.13±7.06)%,P＜0.05。IDO评分与淋巴管侵犯和淋巴结转移存在相关性,分别为P＜0.01和P＜0.05。结论:IDO高表达提示淋巴管侵犯或者淋巴结转移,食管癌处于进展期,因此建议将其作为食管癌进展情况的评估指标之一。     

PD-1在肝细胞癌肿瘤浸润淋巴细胞中的表达及与预后的相关性

背景与目的:程序性死亡[蛋白]-1(programmed death-1,PD-1)在调节外周免疫耐受中发挥重要作用,PD-1在肝细胞癌(hepatocellular carcinoma,HCC)肿瘤浸润淋巴细胞中的表达状态与效应细胞CD8+T淋巴细胞的关系尚不清楚,探讨HCC肿瘤浸润淋巴细胞中PD-1的表达及预后意义...     

The association between measures of progression and survival in castrate-metastatic prostate cancer.

PURPOSE: To explore the association between progression-free survival and overall survival time in patients with castration-resistant prostate cancer treated with microtubule-targeted therapies. EXPERIMENTAL DESIGN: We retrospectively studied patients treated in three trials evaluating a taxane or an epothilone for progressive castration-resistant prostate cancer. Study subjects were 98 patients with bone metastases; 63 of them also had soft tissue lesions. All scans were reviewed independently. Associations of radiographic progression-free survival and prostate-specific antigen (PSA) progression-free survival with survival time were measured using Kendall's tau, adjusted for right censoring. A smoothing procedure was applied to estimate Kendall's tau within each neighborhood of the follow-up process. RESULTS: The overall associations between progression-free survival time and overall survival time were moderate: 0.4 for radiographic progression-free survival and 0.33 for PSA progression-free survival. The association between radiographic progression-free survival and overall survival was weakest early in the follow-up process, whereas the PSA association was weakest when the progression-free survival-related event (PSA progression, death, or censoring) occurred after 6 months from the start of treatment. CONCLUSIONS: Current measures of progression-free survival time for men with castration-resistant prostate cancer are not strongly concordant with survival time. Factors that attenuate the association include interval censoring and the discontinuation of therapy early in the follow-up due to imaging changes that may not reflect true failure of the treatment. For radiographic progression-free survival, the association may be increased by requiring confirmation of progression with a second scan, as is routinely done when assessing response.     

Klotho expression in epithelial ovarian cancer and its association with insulin-like growth factors and disease progression

Klotho is an anti-aging hormone and is able to suppress the action of IGFs. High IGF activities are associated with cancer risk and tumor progression. Klotho's role in cancer is unknown. To evaluate Klotho expression in ovarian cancer and its association with IGFs and ovarian cancer progression, a clinical follow-up study of 189 ovarian cancer patients was conducted. Patients were recruited from a teaching hospital at University of Turin in Italy. All patients were diagnosed with epithelial ovarian cancer and underwent surgery for the disease. Fresh tumor tissue was collected from each patient during surgery. Patient clinical and pathological information was collected, including patient age at surgery, disease stage, tumor grade, tumor histology, residual tumor size, debulking result, post-operative chemotherapeutic agent, treatment response, follow-up time and survival outcome. Expressions of total and secreted Klotho as well as IGFs in tumor tissue were analyzed using quantitative real-time PCR. Survival analysis was performed to evaluate the association of Klotho expression with the risk of disease progression and death using Cox proportional hazards regression model. High expression of secreted Klotho was associated with increased risk of disease progression and death. These associations were independent of patient clinical and pathological characteristics. Expression of secreted Klotho was positively correlated with the expression of IGF-I and IGFBP-3 but not with IGF-II. In conclusion, Klotho expression is associated with epithelial ovarian cancer progression, and the protein may serve as an independent marker for ovarian cancer prognosis. Klotho's role in cancer warrants further elucidation.     

A correlation between the expression of CD 8 antigen and specific cytotoxicity of tumor-infiltrating lymphocytes

Tumor-infiltrating lymphocytes (TIL) from six gynecologic malignant tumors (two uterine cervical cancers, two ovarian serous cystadenocarcinomas, and two uterine corpus cancers), cultured in the presence of recombinant interleukin 2, were assayed for their cytotoxic activities against various fresh tumor cells including autologous tumors. A clear correlation between phenotype and cytotoxic activity of TIL was observed. Four of six TIL preparations exhibited strong cytotoxic activity against autologous fresh tumor target cells, and were all CD8+. In contrast, cytotoxic activity was not detected in any of the CD4+ TIL preparations. The cytotoxic activities of the CD8+ TIL preparations were highly specific; only autologous fresh tumor cells were lysed. This result is consistent with the notion that TIL are of a different cell lineage from lymphokine-activated killer cells which are antigen-nonspecific and CD8-. Instead, TIL appear to be of cytotoxic T cell lineage that is highly antigen-specific and CD8+. To explore the potential for clinical use, we have attempted to augment the cytotoxic activities of these CD8+ TIL by treatment of the target tumor cells with gamma interferon (IFN) in vitro, hoping that elevated expression of MHC class I gene products on the cell surface would enhance their recognition. It was observed that brief treatment of freshly prepared tumor cells in vitro with gamma-IFN resulted in augmentation of the expression of MHC class I gene products, and the treated tumor cells were more susceptible to lysis by TIL than untreated cells.     

Immunologic impairment in patients with non-lymphoid cancer: correlation with the tumoral stage, response to treatment and survival.

The cellular immunity has been studied in 121 patients by solid nonlymphoid tumors, and in 50 healthy patients, 11 with benign tumors, with the use of techniques of in vivo dinitrochlorobenzene (DNCB) and in vitro lymphocyte response to phytohemagglutinin to observe the correlation between both tests and the clinical stage of the disease, the response to chemotherapy and surgery, prognosis, and survival. Patients with anergy presented tumoral irresectability, lack of response to chemotherapy, advanced disease, and limited survival. In the patients with good immune response, the disease was limited, responding with greater frequency to therapy and presenting a higher rate of survival. Consequently, the immunologic study of a neoplastic patient can guide us toward a therapeutic behavior and a prognosis.     

Loss of tumoral expression of soluble IL-6 receptor is associated with disease progression in colorectal cancer

Background:

Interleukin-6 (IL-6) binds both the membrane and soluble forms of the IL-6 receptor (sIL-6R), which induces a complex with gp130, and proliferation of tumour cells. The aim of this study is to clarify the relationship between tumoral sIL-6R expression and disease progression in colorectal cancer patients.

Methods:

We measured tissue concentrations of sIL-6R in tumour and normal mucosa from 161 colorectal cancer patients undergoing surgery, and in supernatants from colon cancer cell lines. The expression of IL-6, IL-6R and gp130 was evaluated by immunohistochemical analysis.

Results:

Loss of tumour expression of sIL-6R as defined by sIL-6R Ca/N ratio <1.0 was significantly associated with factors reflecting disease progression, and was an independent prognostic factor not only in all the patients in this study, but also in the patients with curative intent. Colon cancer cell lines produced sIL-6R in vitro, and the production of sIL-6R in cancer cell lines was stimulated by cytokine stimulation. Immunohistochemistry revealed that loss of tumour expression of sIL-6R was significantly inversely correlated with intense IL-6 expression in the cytoplasm of cancer cells. In addition, tumoral IL-1β expression was significantly correlated with sIL-6R expression.

Conclusion:

Loss of tumour expression of sIL-6R is associated with colorectal cancer disease progression.     

High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma

Medullary breast cancer (MBC) is a basal-like breast carcinoma (BLBC) with a favourable outcome, whereas nonmedullary BLBC has a poor prognosis. Tumour infiltrating lymphocytes (TILs) are present in both MBC and BLBC. We hypothesized that the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) could modulate the TILs effects among these tumours and explain their different outcomes. The amount of TILs and IDO expression were analysed using immunohistochemistry (IHC) in 155 BC cases including MBC (n = 17), atypical MBC (n = 13) and non-MBC (n = 125). Messenger RNA expression of the INDO gene, which encodes IDO, was measured in 262 cases from our institution. INDO mRNA expression and histoclinical data of 1,487 BC cases were collected from public databases. IDO immunostaining was present in both neoplastic and stromal cells in 100% of MBC and was associated with histological medullary features among non-MBC cases. There was a significant correlation between IDO positivity and TIL amounts. In our series including mostly grade-3 BC, IDO immunostaining was the most significant marker (p = 0.02) associated with better survival in multivariate analysis. Among our 262 analysed BC cases, INDO mRNA showed significant overexpression in BLBC as compared to luminal A tumours, and in MBC as compared to basal-like non-MBC. In the pooled series of 1,749 BC cases, INDO mRNA was overexpressed in BLBC and was the most significant predictor of better survival in this subtype using multivariate analysis (p = 0.0024). In conclusion, high IDO expression is associated with morphological medullary features and has an independent favourable prognostic value in BLBC.