• Adult
• Aged
• Aged, 80 and over
• Female
• Humans
• Male
• Middle Aged
• Young Adult
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Biomarkers, Tumor
• Hematologic Neoplasms/drug therapy
• Hematologic Neoplasms/pathology
• Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
• Ipilimumab/administration & dosage
• Neoplasms/drug therapy
• Neoplasms/pathology
• Nivolumab/administration & dosage
• Treatment Outcome

• Eosinophils
• Immunosuppression
• Macrophages
• Myeloid cells
• Neutrophils
• Therapeutic target

• Humans
• Neoplasms/therapy
• Neoplasms/immunology
• Neoplasms/pathology
• Neoplasms/metabolism
• Neoplasms/etiology
• Myeloid Cells/metabolism
• Myeloid Cells/immunology
• Animals
• Tumor Microenvironment/immunology
• Immunotherapy/methods
• Myeloid-Derived Suppressor Cells/immunology
• Myeloid-Derived Suppressor Cells/metabolism

• 2021R1A2C2003277 National Research Foundation of Korea
• CRC TRR332 project A05 Deutsche Forschungsgemeinschaft
• 536993790 Deutsche Forschungsgemeinschaft
• ZELL-THEMA European Regional Development Fund
• N 21366 Fondazione AIRC per la ricerca sul cancro ETS
• Universitätsklinikum Essen (8912)

• AllergoOncology
• allergy
• basophils
• cancer
• eosinophils
• granulocytes
• mast cells
• neutrophils

• Humans
• Mast Cells/immunology
• Mast Cells/metabolism
• Neoplasms/immunology
• Neoplasms/therapy
• Hypersensitivity/immunology
• Hypersensitivity/therapy
• Hypersensitivity/etiology
• Granulocytes/immunology
• Granulocytes/metabolism
• Tumor Microenvironment/immunology
• Animals
• Disease Susceptibility

• MR/L023091/1 Medical Research Council
• MR/V049445/1 Medical Research Council

• Colon cancer
• M2 macrophage-related genes
• Macrophages
• Risk model

• Humans
• Colonic Neoplasms/pathology
• Colonic Neoplasms/immunology
• Colonic Neoplasms/genetics
• Prognosis
• Macrophages/immunology
• Tumor Microenvironment
• Male
• Female
• Gene Expression Regulation, Neoplastic

• Holo IDO1/TDO2 dual inhibitor
• MD simulations
• MM-GBSA binding free energy analysis
• cancer immunotherapy
• consensus virtual screening

• HGSOC
• IDO1
• Ovarian cancer
• Prognostic marker
• TILs

• Humans
• Female
• Ovarian Neoplasms/pathology
• Lymphocytes, Tumor-Infiltrating
• Prognosis
• Carcinoma, Ovarian Epithelial/pathology
• RNA, Messenger
• Tumor Microenvironment/genetics

• Cancer
• Innate immunity
• Microbiome
• Oncobiome
• Tumor microenvironment

• AC092667.2
• NOX4
• RP11-349A8.3
• immune subtype
• infiltrating immune cells
• lncRNAs
• pancreatic cancer
• prognostic model

• NF-κB
• immunosurveillance
• immunotherapy
• lung cancer
• targeted therapy

• Eosinophil
• cardiovascular disease
• count
• epidemiology
• risk

• R01 HL136659 NHLBI NIH HHS
• R21 AG058738 NIA NIH HHS
• R33 AG058738 NIA NIH HHS

• antibody
• graft
• immune response
• immune tolerance
• immunosuppression
• indoleamine 2,3-dioxygenase (IDO1)
• kidney transplant
• kynurenine pathway
• rejection

• C160.22.080 Wrocław Medical University

Immunotherapy is increasingly becoming a success strategy for oncology treatment. Indoleamine-2,3-dioxygenase1 (IDO1) is a tryptophan-degrading enzyme involved in immunological escape mechanisms, which is considered as a potential target for tumor therapy. However, the clinical efficacy of IDO1 inhibitors is not promising. Therefore, there is an urgent to investigate the mechanism between chemical drugs with antitumor effects and IDO1-mediated immunosuppression. The Chinese medicine AS-IV exerts antitumor effects with many advantages, including fewer toxic side effects and immunomodulatory effects. We noted the lack of studies of AS-IV on benign tumors. Therefore, our study demonstrates the Inhibitory effect of AS-IV on ULMs and elucidates the underlying mechanism.

Astragaloside IV (AS-IV) is a chemical found in traditional Chinese medicine called Astragalus membranaceus (Fisch.) Bunge that has antitumor properties. However, the roles and mechanisms of AS-IV in uterine leiomyomas (ULMs) are unclear. The immunosuppressive enzyme indoleamine-2,3-dioxygenase-1 (IDO1) is involved in tumor formation. IDO1 is a new and reliable prognostic indicator for several cancers. In this work, AS-IV was applied to ULM cells in various concentrations. CCK-8, immunofluorescence, and flow cytometry were used to examine the proliferation and apoptosis of ULM cells caused by AS-IV. After lentiviral vector transduction with IDO1 short hairpin RNA (shRNA), the knockdown and overexpression of IDO1 were stable in ULM cells. To verify the antitumor effect of AS-IV in vivo, we established a rat model of uterine leiomyoma. HE staining, Masson staining, and transmission electron microscopy were used to observe pathological changes in the uterus, and the levels of serum sex hormones were measured by radio immune assay (RIA). The levels of CD3+T, CD4+T, and CD25+ Foxp3+Treg in rat peripheral blood were detected by flow cytometry. Western blotting and immunohistochemistry were used to examine protein expression. We found that AS-IV dramatically increased the apoptotic rate of ULM cells and reduced viability in a time- and dosage-dependent manner. After sh-IDO1 lentiviral transfection, we discovered that knocking down IDO1 reversed the effects of AS-IV on ULM cell proliferation and autophagy. We also found that AS-IV can effectively inhibit the growth of ULMs in vivo. AS-IV may promote apoptosis and autophagy in ULMs by activating PTEN/PI3K/AKT signaling through inhibition of IDO1. These findings imply that AS-IV exerts antifibroid effects, and the underlying mechanism may be IDO1, which is involved in proliferation, apoptosis, and autophagy.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is commonly expressed by cancers as a mechanism for evading the immune system. Preclinical and clinical studies have indicated the potential of combining IDO1 inhibitors with immune therapies for the treatment of cancer, strengthening an interest in the discovery of novel dioxygenase inhibitors for reversing tumour-mediated immune suppression. To facilitate the discovery, development and investigation of novel small molecule inhibitors of IDO1 and its hepatic isozyme tryptophan dioxygenase (TDO2), murine tumour cells were engineered to selectively express either murine or human IDO1 and TDO2 for use as tools to dissect both the species specificity and isoenzyme selectivity of newly discovered inhibitors. Lewis lung carcinoma (LLTC) lines were engineered to express either murine or human IDO1 for use to test species selectivity of the novel inhibitors; in addition, GL261 glioma lines were engineered to express either human IDO1 or human TDO2 and used to test the isoenzyme selectivity of individual inhibitors in cell-based assays. The 20 most potent inhibitors against recombinant human IDO1 enzyme, discovered from a commissioned screening of 40,000 compounds in the Australian WEHI compound library, returned comparable IC₅₀ values against murine or human IDO1 in cell-based assays using the LLTC-mIDO1 and LLTC-hIDO1 line, respectively. To test the in vivo activity of the hits, transfected lines were inoculated into syngeneic C57Bl/6 mice. Individual LLTC-hIDO1 tumours showed variable expression of human IDO1 in contrast to GL261-hIDO1 tumours which were homogenous in their IDO1 expression and were subsequently used for in vivo studies. W-0019482, the most potent IDO1 inhibitor identified from cell-based assays, reduced plasma and intratumoural ratios of kynurenine to tryptophan (K:T) and delayed the growth of subcutaneous GL261-hIDO1 tumours in mice. Synthetic modification of W-0019482 generated analogues with dual IDO1/TDO2 inhibitory activity, as well as inhibitors that were selective for either TDO2 or IDO1. These results demonstrate the versatility of W-0019482 as a lead in generating all three subclasses of tryptophan dioxygenase inhibitors which can be applied for investigating the individual roles and interactions between IDO1 and TDO2 in driving cancer-mediated immune suppression.

Eosinophils are rare, multifunctional granulocytes. Their growth, survival, and tissue migration mainly depend on interleukin (IL)-5 in physiological conditions and on IL-5 and IL-33 in inflammatory conditions. Preclinical evidence supports an immunological role for eosinophils as innate immune cells and as agents of the adaptive immune response. In addition to these data, several reports show a link between the outcomes of patients treated with immune checkpoint inhibitors (ICI) for advanced cancers and blood eosinophilia. In this review, we present, in the context of non-small cell lung cancer (NSCLC), the biological properties of eosinophils and their roles in homeostatic and pathological conditions, with a focus on their pro- and anti-tumorigenic effects. We examine the possible explanations for blood eosinophilia during NSCLC treatment with ICI. In particular, we discuss the value of eosinophils as a potential prognostic and predictive biomarker, highlighting the need for stronger clinical data. Finally, we conclude with perspectives on clinical and translational research topics on this subject.

• biomarkers
• eosinophils
• immunotherapy
• non-small cell lung cancer
• predictive value
• prognostic value

• Biomarkers
• Carcinoma, Non-Small-Cell Lung/pathology
• Eosinophils/pathology
• Humans
• Immune Checkpoint Inhibitors
• Immunotherapy
• Lung Neoplasms/pathology

• cancer
• immune cells
• immune evasion
• immune system
• immunosurveillance
• tumour microenvironment

Tertiary lymphoid structures (TLSs) are used as biomarkers in many cancers for predicting the prognosis and assessing the response to immunotherapy. In Merkel cell carcinoma (MCC), TLSs have only been examined in MCPyV-positive cases. Here, we examined the prognostic value of the presence or absence of TLSs in 61 patients with MCC, including MCPyV-positive and MCPyV-negative cases. TLS-positive samples had a significantly better prognosis than TLS-negative samples. MCPyV-positive samples had a good prognosis with or without TLSs, and MCPyV-negative/TLS-positive samples had a similarly good prognosis as MCPyV-positive samples. Only MCPyV-negative/TLS-negative samples had a significantly poor prognosis. All cases with spontaneous regression were MCPyV-positive/TLS-positive. We also performed a comprehensive analysis of the chemokines associated with TLS formation using next-generation sequencing (NGS). The RNA sequencing results revealed 5 chemokine genes, CCL5, CCR2, CCR7, CXCL9, and CXCL13, with significantly high expression in TLS-positive samples compared with TLS-negative samples in both MCPyV-positive and MCPyV-negative samples. Only 2 chemokine genes, CXCL10 and CX3CR1, had significantly different expression levels in the presence or absence of MCPyV infection in TLS-negative samples. Patients with high CXCL13 or CCL5 expression have a significantly better prognosis than those with low expression. In conclusion, the presence of TLSs can be a potential prognostic marker even in cohorts that include MCPyV-negative cases. Chemokine profiles may help us understand the tumor microenvironment in patients with MCPyV-positive or MCPyV-negative MCC and may be a useful prognostic marker in their own right.

• Merkel cell carcinoma (MCC)
• biomarker
• chemokine
• cohort study
• tertiary lymphoid structure (TLS)
• tumor micreoenvironment (TME)

To investigate whether eosinophils and other white blood cell subtypes could be used as response and prognostic markers to anti-Programmed cell Death-1 or anti-PD-Ligand-1 treatments in non-small cell lung cancer patients.

We retrospectively analyzed data from the NSCLC patients consecutively treated at our hospital with a PD-1/PD-L1 inhibitor in monotherapy for advanced disease. A total of 191 patients were evaluated at three time-points to investigate any relation between tumor response and WBC counts.

Baseline WBC and subtypes did not differ according to the type of response seen under treatment. A higher relative eosinophil count (REC) correlated with more objective responses (p = 0.019 at t1 and p = 0.014 at t2; OR for progression = 0.54 and 0.53, respectively) independently of the smoking status, PD-L1 status, and immune-related toxicity (IRT). Higher REC was also associated with a longer duration of treatment (p = 0.0096). Baseline absolute neutrophil count was prognostic (p = 0.049). At t1 relative lymphocytes, absolute and relative neutrophils, and neutrophil-to-lymphocyte ratio were prognostic (p = 0.044, p = 0.014, p = 0.0033, and p = 0.029, respectively).

Our results show that in NSCLC patients anti-PD-1/PD-L1 therapy induces an early increase only in blood eosinophils, more prominent in responding patients and independent of the smoking status, PD-L1 status, and IRT. Eosinophils are also associated with a longer duration of treatment. Furthermore, our data support a prognostic role of neutrophils, lymphocytes, and their ratio for NSCLC patients with advanced disease treated with PD(L)-1 blockade.

• Checkpoint inhibitors
• Non-small cell lung cancer
• PD-1 inhibitors
• Predictive marker
• Prognostic marker
• White blood cells

• adaptive immunity
• autoimmune disease
• autoimmune endocrinopathies
• autoimmune thyroiditis
• indoleamine 2,3-dioxygenase 1 (IDO1)
• innate immunity
• kynurenine pathway (KP)
• type 1 diabetes mellitus (T1DM)

• Adaptive Immunity/genetics
• Autoimmune Diseases/genetics
• Autoimmune Diseases/immunology
• Endocrine System Diseases/genetics
• Endocrine System Diseases/immunology
• Humans
• Immunity, Innate/immunology
• Kynurenine/genetics
• Kynurenine/immunology
• Kynurenine/metabolism
• Signal Transduction/immunology

M4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.

In preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.

In mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).

There were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.

Trial registration number NCT03306420.

• clinical trials as topic
• drug evaluation, preclinical
• immune evasion
• immunomodulation
• indoleamine-pyrrole 2,3,-dioxygenase

• Th1 responses
• Th2 responses
• bacteria
• eosinophils
• homeostasis
• microbiota

• Animals
• Bordetella Infections/immunology
• Bordetella bronchiseptica/immunology
• Eosinophils/immunology
• Helicobacter Infections/immunology
• Helicobacter pylori/immunology
• Humans
• Microbiota/immunology
• Th17 Cells/immunology
• Th2 Cells/immunology

• P01 AI127335 NIAID NIH HHS
• P20 GM134974 NIGMS NIH HHS
• 1P20-GM134974-0181 NIH HHS

Metabolism is the process by which living organisms and cells generate energy to sustain life. At the organismal level, metabolic homeostasis is a tightly controlled balance between energy consumption and energy expenditure. Many studies have shown that disruption of this homeostasis leads to an inflammatory phenotype within adipose tissue. The aim of this review is to provide an overview of the dynamic metabolic interplay within adipose tissue and its implications for cancer progression and metastasis.

Disruption of metabolic homeostasis at the organismal level can cause metabolic syndrome associated with obesity. The role of adipose tissue in cancer has been investigated over the last several decades with many studies implicating obesity as a risk factor for the development of cancer. Adipose tissue contains a diverse array of immune cell populations that promote metabolic homeostasis through a tightly controlled balance of pro- and anti-inflammatory signals. During obesity, pro-inflammatory cell types infiltrate and expand within the adipose tissue, exacerbating metabolic dysfunction. Some studies have now shown that the intracellular metabolism of immune cells is also deregulated by the lipid-rich environment in obesity. What is not fully understood, is how this may influence cancer progression, metastasis, and anti-tumor immunity. This review seeks to highlight our current understanding of the effect of adipose tissue on immune cell function and discuss how recent results offer new insight into the role that adipose tissue plays in cancer progression and anti-tumor immunity.

• adipocyte
• adipose tissue
• cancer
• immune cell
• immunometabolism
• metastasis

• Cancer-immunotherapy
• Drug discovery
• IDO1
• Inhibitor-screening
• TDO2
• Tryptophan dioxygenases

• Drug Discovery
• Enzyme Inhibitors/chemistry
• Enzyme Inhibitors/pharmacology
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
• Reproducibility of Results
• Structure-Activity Relationship

IDO1-mediated immune escape can lead to the malignant progression of tumors. However, the precise mechanism of IDO1 remains unclear. This study showed that IDO1 can bind to GBP1 and increase the extracellular secretion of IDO1 with the assistance of GBP1, thereby promoting the malignant proliferation and metastasis of lung cancer. In vitro study showed that the high expression levels of IDO1 and GBP1 in lung cancer cells promoted cell invasion and migration. In vivo study revealed that knock-down of IDO1 and GBP1 inhibited tumor growth and metastasis. In addition, Astragaloside IV reduces the extracellular secretion of IDO1 by blocking the interaction of IDO1 and GBP1, thereby reducing T cell exhaustion and inhibiting tumor progression. These results suggest that blocking the extracellular secretion of IDO1 may prevent T cell exhaustion and thereby enhance the effect of PD-1 inhibitors on cancer treatment.

• GBP1
• PD-1
• astragaloside IV
• indoleamine 2,3-dioxygenase 1 (IDO1)
• lung cancer

There is an urgent need for identification of new prognostic markers and therapeutic targets for non-small cell lung cancer (NSCLC). In this study, we evaluated immune cells markers in 100 NSCLC specimens. Immunohistochemical analysis revealed no prognostic value for the markers studied, except CD163 and CD206. At the same time, macrophage markers iNOS and CHID1 were found to be expressed in tumor cells and associated with prognosis. We showed that high iNOS expression is a marker of favorable prognosis for squamous cell lung carcinoma (SCC), and NSCLC in general. Similarly, high CHID1 expression is a marker of good prognosis in adenocarcinoma and in NSCLC in general. Analysis of prognostic significance of a high CHID1/iNOS expression combination showed favorable prognosis with 20 months overall survival of patients from the low CHID1/iNOS expression group. For the first time, we demonstrated that CHID1 can be expressed by NSCLC cells and its high expression is a marker of good prognosis for adenocarcinoma and NSCLC in general. At the same time, high expression of iNOS in tumor cells is a marker of good prognosis in SCC. When used in combination, CHID1 and iNOS show a very good prognostic capacity for NSCLC. We suggest that in the case of lung cancer, tumor-associated macrophages are likely ineffective as a therapeutic target. At the same time, macrophage markers expressed by tumor cells may be considered as targets for anti-tumor therapy or, as in the case of CHID1, as potential anti-tumor agents.

• chitinase-like protein
• lung cancer
• macrophage
• prognosis
• stroma

• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Biomarkers, Tumor/metabolism
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Carrier Proteins/metabolism
• Female
• Humans
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Male
• Middle Aged
• Nitric Oxide Synthase Type II/metabolism
• Prognosis

• Eosinophils
• Immunity
• Lung
• Pulmonary
• Respiratory diseases
• Targeted therapies

• fine-tuning
• immunosuppression
• immunotherapy
• mechanisms
• tumour
• tumour microenvironment

• Clinical Trials as Topic
• Cytokines/metabolism
• Humans
• Immunosuppression Therapy
• Metabolome
• Neoplasms/immunology
• Tumor Microenvironment/immunology

• 1-methyl-D-tryptophan (1-MT)
• Aryl hydrocarbon receptor (AhR)
• IDO inhibitors
• Indoleamine 2,3-dioxygenase 1 (IDO1)
• Indoleamine 2,3-dioxygenase 2 (IDO2)
• Interferon-gamma (IFN-γ)
• Kynurenine (Kyn)
• Nitric oxide (NO)
• Tryptophan (Trp)
• Tryptophan 2,3-dioxygenase (TDO)

• Acceleration
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
• Kynurenine
• Protein Kinases
• Tryptophan

Forkhead box P3 (FOXP3) is a specific marker for immunosuppressive regulatory T (T-reg) cells. T-regs and an immunosuppressive enzyme, indoleamine 2,3-dioxygenase (IDO), are associated with advanced disease in cancer.

To evaluate the co-expression of FOXP3 and IDO in triple negative breast cancer (TNBC) with respect to hormone-positive breast cancer patients from Pakistan.

Immunohistochemistry was performed to analyze the expression of FOXP3, IDO, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor on tissues of breast cancer patients (n = 100): Hormone-positive breast cancer (n = 51) and TNBC (n = 49). A total of 100 patients were characterized as FOXP3 negative vs positive and further categorized based on low, medium, and high IDO expression score. Univariate and multivariate logistic regression models were used.

Out of 100 breast tumors, 25% expressed FOXP3 positive T-regs. A significant co-expression of FOXP3 and IDO was observed among patients with TNBC (P = 0.01) compared to those with hormone-positive breast cancer. Two variables were identified as significant independent risk factors for FOXP3 positive: IDO expression high (adjusted odds ratio (AOR) 5.90; 95% confidence interval (CI): 1.22-28.64; P = 0.03) and TNBC (AOR 2.80; 95%CI: 0.96-7.95; P = 0.05).

Our data showed that FOXP3 positive cells might be associated with high expression of IDO in TNBC patients. FOXP3 and IDO co-expression may also suggest its involvement in disease, and evaluation of FOXP3 and IDO expression in TNBC patients may offer a new therapeutic option.

• Forkhead box P3
• Indoleamine 2,3-dioxygenase
• Triple negative breast cancer
• T-regs
• Immunotherapy
• Cancer

• Cancer
• Immune system
• Indoleamine 2,3-dioxygenase
• Inhibitors
• Kynurenine pathway
• Multiple activities
• Tryptophan 2,3-dioxygenase

• Eosinophils
• oral squamous cell carcinoma
• tumor associated blood eosinophilia
• tumor-associated tissue eosinophilia

• Animals
• Biomarkers
• Chemotaxis, Leukocyte/genetics
• Chemotaxis, Leukocyte/immunology
• Combined Modality Therapy
• Disease Management
• Disease Susceptibility
• Eosinophils/immunology
• Eosinophils/metabolism
• Eosinophils/pathology
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/therapy
• Signal Transduction
• Tumor Microenvironment/genetics
• Tumor Microenvironment/immunology

• IDO—indoleamine 2,3-dioxygenase
• immune regulation
• inflammation
• liquid biopsy
• prognostic marker
• prostate cancer
• radical prostatectomy

• Humans
• Male
• Biomarkers, Tumor
• Cell-Free Nucleic Acids
• Gene Expression
• Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
• Indoleamine-Pyrrole 2,3,-Dioxygenase/urine
• Liquid Biopsy
• Neoplasm Grading
• Prognosis
• Prostatectomy
• Prostatic Neoplasms/diagnosis
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/surgery
• Prostatic Neoplasms/urine
• ROC Curve

• Uveitis
• drug toxicity
• immunotherapy
• multidisciplinary coordination of care
• ocular adverse events

• Cancer imaging
• IDO
• Kynurenine pathway
• PET
• Tryptophan metabolism

Gynaecologic and breast cancers share some similarities at the molecular level. The aims of our study are to highlight the similarities and differences about IDO1, an important immune‐related gene in female cancers. The NGS data from TCGA of cervical squamous cell carcinoma (CESC), ovarian serous cystadenocarcinoma (OV), uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS) and breast invasive carcinoma (BRCA) were analysed to identify molecular features, and clinically significant and potential therapeutic targets of IDO1. We found IDO1 was significantly up‐regulated in four gynaecologic cancers and breast cancer. According to breast cancer PAM50 classification scheme, IDO1 expression was higher in tumours of basal than other subtypes and showed better survival prognosis in BRCA and OV. Through immune infiltration analysis, we found a strong correlation between IDO1 and immune cell populations especially for dendritic cells and T cells. In addition, we investigated the association between IDO1 and tumour mutation burden (TMB) and found that IDO1 was significantly correlated with TMB in BRCA and CESC. GSVA revealed that hallmarks significantly correlated with IDO1 were involved in interferon gamma response, allograft rejection and inflammatory response. We also found PD‐L1 and LAG3 were highly positive related to IDO1 in gynaecologic cancers when comparing with their corresponding normal tissues. Our results indicated that IDO1 participated in anti‐tumour immune process and is correlated with mutation burden. These findings may expand our outlook of potential anti‐IDO1 treatments.

• IDO1
• TMB
• breast cancers
• gynaecologic cancers
• immunotherapy

• anemia
• cancer
• depression
• fatigue
• inflammation
• kynurenine
• tryptophan

• Anemia/metabolism
• Animals
• Depression/metabolism
• Fatigue/metabolism
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
• Inflammation/metabolism
• Kynurenine/metabolism
• Neoplasms/metabolism
• Tryptophan/metabolism

• Prostate cancer
• prognostic markers

• dendritic cell
• gastric cancer
• indoleamine 2,3-dioxygenase
• regulator T cell

• Cancer
• Disease
• Neurological disorders
• Physiology
• Psychiatric disorders
• Tryptophan

• Cancer
• Eosinophils
• Immunotherapy
• PIVAC 17
• Prognostic marker

• Biomarkers
• Cytotoxicity, Immunologic
• Eosinophils/immunology
• Humans
• Hypersensitivity/immunology
• Immunotherapy/methods
• Neoplasms/immunology
• Parasitic Diseases/immunology
• Prognosis
• Tumor Microenvironment

• RTG2099 Deutsche Forschungsgemeinschaft
• CA181 Deutsches Krebsforschungszentrum

Immune dysfunction in breast cancer patients is well established. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that is linked with progression of cancer. IDO is overexpressed in triple-negative breast cancer (TNBC) cases.

We conducted the first study to analyze IDO expression and overall survival in breast cancer cases in Pakistan. Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), and human EGF receptor 2 (HER2) was evaluated by immunohistochemistry. Formalin-fixed paraffin-embedded breast cancer tissues of 100 (TNBC, n=49 and non-TNBC, n=51) patients were obtained from Shaukat Khanum Memorial Cancer Hospital and Research Centre. IDO expression was analyzed in association with clinicopathological features and overall survival. A total of 100 patients were classified based on the ordinal IDO score variables as low, medium, and high. In addition, overall mean age and SD of patients was 48.28±11.82.

Immunohistochemical analysis showed that high IDO was observed in the TNBC patients (65.3%) compared to that in the non-TNBC patients (33.3%). Multivariable analyses showed that TNBC was an independent risk factor for high IDO expression. Overall survival was also significantly associated with IDO score.

Our study showed that IDO protein expression is higher in TNBC patients (P<0.01) and may suggest its role in disease pathogenesis. TNBC might be effectively treated with IDO inhibitors. Furthermore, high IDO expression is considerably associated with overall decreased patient survival. IDO might be utilized as a potential biomarker and immunotherapeutic target in breast cancer patients.

• 3-dioxygenase
• Pakistan
• breast cancer
• indoleamine 2
• triple-negative breast cancer

Background: Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan (Trp) metabolism, is generally considered to be an immunosuppressive molecule. The prognostic role of IDO expression in tumor has not been well studied in non-small cell lung cancer (NSCLC) and even not been reported in adenosquamous lung carcinoma (AdSqLC). Herein, the aim of this study is to investigate the prognostic significance of IDO expression in patients with AdSqLC.

Patients and Methods: We conducted immunohistochemical analyses of IDO expression, as well as CD3 and CD8 expression, in 183 primary tumor tissue samples from patients with AdSqLC treated at our institution between July 1999 and September 2014. Patients' clinicopathological characteristics were retrospectively reviewed. Survival analysis was performed in the entire cohort of patients and those who received radical resection, respectively.

Results: IDO was expressed in 146 (79.8%) tumor samples. A higher level of IDO expression was significantly associated with increased CD8+ tumor-infiltrating lymphocytes (TILs) in tumor tissues (P<0.001). Surprisingly, overall survival (OS) was significantly better for patients with high IDO expression (hazard ratio (HR)= 0.505; confidence interval (CI)= 0.329-0.775; P=0.002) for the entire cohort. In patients who were unable to be treated with radical resection, IDO expression had no effect on OS (P=0.598). In contrast, a significant, independent association between high expression of IDO and better OS (HR=0.469; CI=0.290-0.758; P=0.002) was identified in patients who received radical resection.

Conclusions: IDO is expressed in most AdSqLC tissues, with a higher level of IDO expression associated with an occurrence of CD8+ TILs. Moreover, IDO expression in tumor promises to serve as a strongly independent favorable prognostic factor, particularly in patients who received radical resection.

• 3-dioxygenase
• Indoleamine 2
• lung cancer
• prognosis
• radical resection