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Gulakar B, Sebin SO, Laloglu E, Tanyeli A, Güler MC, Erbas E, Can S. New Potential Agent in Ovarian Ischemia Reperfusion Injury: Alpha Pinene. J Biochem Mol Toxicol 2025; 39:e70318. [PMID: 40421799 DOI: 10.1002/jbt.70318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Revised: 04/14/2025] [Accepted: 05/19/2025] [Indexed: 05/28/2025]
Abstract
Ovarian torsion causes problems such as infertility in women due to ischemia-reperfusion (I/R) injury. α-Pinene (AP) is a monoterpene with known anti-inflammatory, antioxidant, and antiapoptotic impacts. In the present investigation, the protective impact of AP was examined in the ovarian I/R model. 28 Wistar-Albino female rats were used in the study. TNF-α, IL-1β, IL-10, MDA, IMA, SOD, and SIRT-1 levels were determined in ovarian tissue by ELISA method. Histopathological and immunohistochemical analyses were conducted to determine Bcl-2, Caspase-3, LC3B, and NFκB levels in ovarian tissues. TNF-α, IL-1β, IMA, and MDA levels were reduced in the treatment groups than the I/R group dose-dependent, while IL-10, SOD, and SIRT-1 levels increased substantially. Caspase-3 immunoreactivity declined in the treatment groups while Bcl-2 levels increased. LC3B and NFκB levels, which rise with I/R injury, were reduced considerably in the treatment groups. In addition, hemorrhage, edema, vascular congestion, and follicular degeneration due to I/R injury decreased in the treatment groups. The present investigation shows that AP has anti-inflammatory, antiapoptotic, and autophagy inhibitory effects against I/R damage in ovarian tissues and reduces oxidative stress. The results indicate that AP may be a potential protective agent in clinical use. Further research is needed before AP can be used in the clinic.
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Affiliation(s)
- Basak Gulakar
- Department of Physiology, Faculty of Medicine, Kafkas University, Kars, Turkey
| | - Saime Ozbek Sebin
- Department of Physiology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Esra Laloglu
- Department of Biochemistry, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Ayhan Tanyeli
- Department of Physiology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Mustafa Can Güler
- Department of Physiology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Elif Erbas
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
| | - Serpil Can
- Department of Physiology, Faculty of Medicine, Kafkas University, Kars, Turkey
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2
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Yu W, Yuan X, Zhai P, Li X, Han C. Effects of Trichinella spiralis excretory-secretory antigens on expression of indoleamine 2, 3-dioxygenase on dendritic cells in vitro. Parasite 2025; 32:26. [PMID: 40239041 PMCID: PMC12002673 DOI: 10.1051/parasite/2025018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
Indoleamine 2, 3-dioxygenase (IDO) is a potent immunoenzyme found in dendritic cells (DCs). Research has demonstrated that Trichinella spiralis induces IDO expression in the host immune response through its excretory-secretory (ES) antigens. However, the role of IDO in the immune response to T. spiralis remains unclear. To examine the effects of T. spiralis ES antigens on IDO expression in DCs in vitro, assessments were conducted using qRT-PCR, Western blotting (WB), flow cytometry, and siRNA transfer. The findings indicated that ES antigen stimulation upregulated IDO expression in DCs in vitro. Furthermore, ES antigen significantly enhanced the expression of the proinflammatory cytokines TNF-α and IFN-γ, along with the anti-inflammatory cytokine IL-10, downstream of IDO in DCs. Flow cytometry analysis confirmed that surface molecules CD40, MHC-II, CD80, and CD86 on DCs were upregulated following stimulation with ES antigen and lipopolysaccharide (LPS). Compared to the ES antigen alone, siRNA620 effectively inhibited IDO levels, demonstrating a statistically significant reduction. Continuous stimulation of DCs by ES antigens may lead to immune tolerance through the activation of IDO-mediated inflammation-associated factors. These results suggest that IDO expression in DCs plays a crucial role in T. spiralis infection.
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Affiliation(s)
- Wenhao Yu
- College of Veterinary Medicine, Northeast Agricultural University Harbin China
| | - Xuhong Yuan
- College of Veterinary Medicine, Northeast Agricultural University Harbin China
| | - Peng Zhai
- College of Veterinary Medicine, Northeast Agricultural University Harbin China
| | - Xiaoyun Li
- College of Veterinary Medicine, Northeast Agricultural University Harbin China
| | - Caixia Han
- College of Veterinary Medicine, Northeast Agricultural University Harbin China
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3
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Salmi T, Ameur D, Dali-Sahi M, Dib J, Amraoui N, Kachekouche Y, Dennouni-Medjati N. Exploration of plasma tryptophan levels along with Ki-67 expression binomial investigation for forecasting tumor aggressiveness within invasive ductal breast cancer. J Mol Histol 2024; 56:52. [PMID: 39708255 DOI: 10.1007/s10735-024-10333-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 12/07/2024] [Indexed: 12/23/2024]
Abstract
Ki-67 is a histological marker indicating cancer aggressiveness, while tryptophan (TRP) depletion modulates immune responses, including tumor aggressiveness. The study evaluates Ki-67's predictive value in relation to plasma TRP levels in invasive ductal carcinoma of breast cancer, aiming to improve understanding of tumor characteristics and clinical behavior. A study involving 165 women, measured plasma TRP levels and Ki-67 and analyzed their relationship with tumor aggressiveness markers using statistical analyses and predictive models. Our study highlighted a significant correlation between decreased plasma levels of TRP and a high mitotic index, measured by the Ki-67 marker (Pearson correlation coefficient r = - 0.402; p = 0.011). Tryptophan levels below 40 µmol/L were associated with a Ki-67 level above 15%, suggesting more active tumor growth in patients. Additionally, several risk factors for BC were identified within the studied population. The demographic and clinical characteristics of the participants include an average age of 63 years, plasma glucose levels above 1.2 g/L, and plasma TRP levels below 40 µmol/L, which are associated with an increased risk of BC. Furthermore, various polynomial logistic regression models indicate that TRP levels may be predicted based on Ki-67 expression, providing a promising approach to refine prognostic assessments. The study showed a correlation between low levels of tryptophan (TRP) and a high Ki-67 mitotic index in breast cancer patients, particularly in invasive ductal carcinoma, which is strongly linked to the aggressiveness of the disease. The integration of these markers into routine practice remains a technical and economic challenge.
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MESH Headings
- Tryptophan/blood
- Tryptophan/metabolism
- Humans
- Ki-67 Antigen/blood
- Ki-67 Antigen/metabolism
- Ki-67 Antigen/analysis
- Female
- Breast Neoplasms/blood
- Breast Neoplasms/pathology
- Breast Neoplasms/diagnosis
- Middle Aged
- Carcinoma, Ductal, Breast/blood
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/diagnosis
- Carcinoma, Ductal, Breast/metabolism
- Aged
- Biomarkers, Tumor/blood
- Adult
- Prognosis
- Mitotic Index
- Aged, 80 and over
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Affiliation(s)
- Takwa Salmi
- Department of Biology, University of Tlemcen, 22, Rue Abi Ayed Abdelkrim, Fg Pasteur, B.P 119, 13000, Tlemcen, Algeria
- Analytical Chemistry and Electrochemistry Laboratory, University of Tlemcen, 13000, Tlemcen, Algeria
| | - Djilali Ameur
- Departement of Physics, University of Tlemcen, 22, Rue Abi Ayed Abdelkrim, Fg Pasteur, B.P 119, 13000, Tlemcen, Algeria.
- Laboratory of Theoretical Physics, Faculty of Sciences, University of Tlemcen, 13000, Tlemcen, Algeria.
| | - Majda Dali-Sahi
- Department of Biology, University of Tlemcen, 22, Rue Abi Ayed Abdelkrim, Fg Pasteur, B.P 119, 13000, Tlemcen, Algeria
- Analytical Chemistry and Electrochemistry Laboratory, University of Tlemcen, 13000, Tlemcen, Algeria
| | - Joanna Dib
- Analytical Chemistry and Electrochemistry Laboratory, University of Tlemcen, 13000, Tlemcen, Algeria
- Departement of Mathematics, University of Tlemcen, 22, Rue Abi Ayed Abdelkrim, Fg Pasteur, B.P 119, 13000, Tlemcen, Algeria
| | - Nawel Amraoui
- Department of Biology, University of Tlemcen, 22, Rue Abi Ayed Abdelkrim, Fg Pasteur, B.P 119, 13000, Tlemcen, Algeria
| | - Youssouf Kachekouche
- Department of Biology, Faculty of Nature and Life Sciences, University of Chlef, Chlef, Algeria
| | - Nouria Dennouni-Medjati
- Department of Biology, University of Tlemcen, 22, Rue Abi Ayed Abdelkrim, Fg Pasteur, B.P 119, 13000, Tlemcen, Algeria
- Analytical Chemistry and Electrochemistry Laboratory, University of Tlemcen, 13000, Tlemcen, Algeria
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4
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Dell’Anno F, Giugliano R, Listorti V, Razzuoli E. A Review on Canine and Human Soft Tissue Sarcomas: New Insights on Prognosis Factors and Treatment Measures. Vet Sci 2024; 11:362. [PMID: 39195816 PMCID: PMC11358912 DOI: 10.3390/vetsci11080362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/26/2024] [Accepted: 08/03/2024] [Indexed: 08/29/2024] Open
Abstract
Soft tissue sarcomas (STSs) represent a diverse group of tumors arising from mesenchymal cells, affecting both humans and animals, including dogs. Although STSs represent a class of rare tumors, especially in humans, they pose significant clinical challenges due to their potential for local recurrence and distant metastasis. Dogs, as a model for human STSs, offer several advantages, including exposure to similar environmental risk factors, genetic diversity among breeds, and the spontaneous development of tumors. Furthermore, canine tumors closely mimic the heterogeneity and complexity of human tumors, making them valuable for research into disease progression and treatment effectiveness. Current treatment approaches for STSs in both dogs and humans primarily involve surgery, radiation therapy, and chemotherapy, with treatment decisions based on tumor characteristics and patient factors. However, the development of novel therapeutic strategies is essential, given the high failure rate of new drugs in clinical trials. To better design new tailored treatments, comprehension of the tumor microenvironment (TME) is fundamental, since it plays a crucial role in STS initiation and progression by modulating tumor behavior, promoting angiogenesis, and suppressing immune responses. Notably, TME features include cancer-associated fibroblasts (CAFs), extracellular matrix (ECM) alterations, and tumor-associated macrophages (TAMs) that, depending on their polarization state, can affect immune responses and thus the patient's prognosis. In this review, new therapeutical approaches based on immunotherapy will be deeply explored as potential treatment options for both dogs and humans with STSs. In conclusion, this review provides an overview of the current understanding of STSs in dogs and humans, emphasizing the importance of the TME and potential treatment strategies.
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Affiliation(s)
- Filippo Dell’Anno
- National Reference Center of Veterinary and comparative Oncology (CEROVEC), Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, 16129 Genova, Italy; (F.D.); (V.L.); (E.R.)
- Department of Public Health, Experimental and Forensic Medicine, Section of Biostatistics and Clinical Epidemiology, University of Pavia, 27100 Pavia, Italy
| | - Roberta Giugliano
- National Reference Center of Veterinary and comparative Oncology (CEROVEC), Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, 16129 Genova, Italy; (F.D.); (V.L.); (E.R.)
| | - Valeria Listorti
- National Reference Center of Veterinary and comparative Oncology (CEROVEC), Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, 16129 Genova, Italy; (F.D.); (V.L.); (E.R.)
| | - Elisabetta Razzuoli
- National Reference Center of Veterinary and comparative Oncology (CEROVEC), Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, 16129 Genova, Italy; (F.D.); (V.L.); (E.R.)
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5
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Chen H, Molberg K, Carrick K, Niu S, Rivera Colon G, Gwin K, Lewis C, Lea J, Panwar V, Zheng W, Castrillon DH, Lucas E. Expression and Prognostic Significance of LAG-3, TIGIT, VISTA, and IDO1 in Endometrial Serous Carcinoma. Mod Pathol 2024; 37:100532. [PMID: 38848896 DOI: 10.1016/j.modpat.2024.100532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/27/2024] [Accepted: 05/29/2024] [Indexed: 06/09/2024]
Abstract
Endometrial serous carcinoma (ESC) is an uncommon, aggressive type of endometrial cancer. While immune checkpoint blockade has emerged as a promising treatment option for endometrial carcinomas, research on the expression of immune checkpoints that could serve as prospective immunotherapy targets in ESC is limited. We examined the prevalence and prognostic value of lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin (Ig) suppressor of T-cell activation (VISTA), and indoleamine 2,3-dioxygenase 1 (IOD1) in 94 cases of ESC and correlated their expression with CD8+ and FOXP3+ tumor-infiltrating lymphocytes (TILs). We observed a positive correlation among LAG-3, TIGIT, and VISTA expressed on immune cells, and among these markers and CD8+ and FOXP3+ TIL densities. In Kaplan-Meier survival analysis, tumors with high levels of LAG-3 and TIGIT expression had better progression-free survival (PFS) and overall survival (OS) than those with lower levels of expression (LAG-3: PFS, P = .03, OS, P = .04; TIGIT: PFS, P = .01, OS, P = .009). In multivariate analysis, only high TIGIT expression was of independent prognostic value for better OS. VISTA expression in immune or tumor cells, and IDO1 expression in tumor cells, did not show a significant association with survival. Our data indicate that LAG-3, TIGIT, and VISTA immune checkpoints have roles in the microenvironment of ESC, and their expression patterns highlight the complex interactions among the different components of this system. High levels of these markers, together with high CD8+ TIL, suggest the potential immunogenicity of a subset of these tumors. Further studies are needed to elucidate the roles of various immune components in the ESC microenvironment and their association with intrinsic tumor properties.
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MESH Headings
- Aged
- Aged, 80 and over
- Female
- Humans
- Middle Aged
- Antigens, CD/metabolism
- B7 Antigens/metabolism
- Biomarkers, Tumor/analysis
- Cystadenocarcinoma, Serous/pathology
- Cystadenocarcinoma, Serous/mortality
- Cystadenocarcinoma, Serous/immunology
- Endometrial Neoplasms/pathology
- Endometrial Neoplasms/immunology
- Endometrial Neoplasms/mortality
- Endometrial Neoplasms/genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Indoleamine-Pyrrole 2,3,-Dioxygenase/analysis
- Lymphocyte Activation Gene 3 Protein
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/pathology
- Prognosis
- Receptors, Immunologic/metabolism
- Tumor Microenvironment/immunology
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Affiliation(s)
- Hao Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Kyle Molberg
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Kelley Carrick
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Shuang Niu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Glorimar Rivera Colon
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Katja Gwin
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Cheryl Lewis
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jayanthi Lea
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Vandana Panwar
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Wenxin Zheng
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Diego H Castrillon
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Elena Lucas
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas.
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6
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Schöniger S, Degner S, Schandelmaier C, Aupperle-Lellbach H, Zhang Q, Schildhaus HU. Immunohistochemical Detection of Indoleamine 2,3-Dioxygenase in Spontaneous Mammary Carcinomas of 96 Pet Rabbits. Animals (Basel) 2024; 14:2060. [PMID: 39061522 PMCID: PMC11274320 DOI: 10.3390/ani14142060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
For mammary carcinomas in pet rabbits, prognostic biomarkers are poorly defined, and treatment is limited to surgical excision. Additional treatment options are needed for rabbit patients for which surgery is not a suitable option. In human breast cancer, the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) represents a prognostic biomarker and possible therapeutic target. This retrospective immunohistochemical study examined IDO1 in 96 pet rabbit mammary carcinomas with known mitotic count, hormone receptor status, and percentage of stromal tumor infiltrating lymphocytes (TILs). Tumors were obtained from 96 pet rabbits with an average of 5.5 years. All rabbits with reported sex (n = 88) were female or female-spayed. Of the carcinomas, 94% expressed IDO1, and 86% had sparse TILs consistent with cold tumors. Statistically significant correlations existed between a higher percentage of IDO1-positive tumor cells, lower mitotic counts, and increased estrogen receptor expression. The threshold for significance was IDO1 staining in >10% of tumor cells. These results lead to the assumption that IDO1 expression contributes to tumorigenesis and may represent a prognostic biomarker and possible therapeutic target also in pet rabbit mammary carcinomas. They also support the value of rabbits for breast cancer research.
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Affiliation(s)
- Sandra Schöniger
- Discovery Life Sciences Biomarker Services GmbH, Germaniastrasse 7, 34119 Kassel, Germany;
| | - Sophie Degner
- Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 33, 04103 Leipzig, Germany
| | - Claudia Schandelmaier
- Laboklin GmbH & Co. KG, Laboratory for Clinical Diagnostics, 97688 Bad Kissingen, Germany; (C.S.); (H.A.-L.)
| | - Heike Aupperle-Lellbach
- Laboklin GmbH & Co. KG, Laboratory for Clinical Diagnostics, 97688 Bad Kissingen, Germany; (C.S.); (H.A.-L.)
- Institute of Pathology, School of Medicine, Technical University of Munich, Trogerstrasse 18, 81675 Munich, Germany
| | - Qian Zhang
- Institute of Anatomy, Experimental Neurobiology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany;
| | - Hans-Ulrich Schildhaus
- Discovery Life Sciences Biomarker Services GmbH, Germaniastrasse 7, 34119 Kassel, Germany;
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7
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Rodríguez-Bejarano OH, Parra-López C, Patarroyo MA. A review concerning the breast cancer-related tumour microenvironment. Crit Rev Oncol Hematol 2024; 199:104389. [PMID: 38734280 DOI: 10.1016/j.critrevonc.2024.104389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/29/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024] Open
Abstract
Breast cancer (BC) is currently the most common malignant tumour in women and one of the leading causes of their death around the world. New and increasingly personalised diagnostic and therapeutic tools have been introduced over the last few decades, along with significant advances regarding the study and knowledge related to BC. The tumour microenvironment (TME) refers to the tumour cell-associated cellular and molecular environment which can influence conditions affecting tumour development and progression. The TME is composed of immune cells, stromal cells, extracellular matrix (ECM) and signalling molecules secreted by these different cell types. Ever deeper understanding of TME composition changes during tumour development and progression will enable new and more innovative therapeutic strategies to become developed for targeting tumours during specific stages of its evolution. This review summarises the role of BC-related TME components and their influence on tumour progression and the development of resistance to therapy. In addition, an account on the modifications in BC-related TME components associated with therapy is given, and the completed or ongoing clinical trials related to this topic are presented.
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Affiliation(s)
- Oscar Hernán Rodríguez-Bejarano
- Health Sciences Faculty, Universidad de Ciencias Aplicadas y Ambientales (U.D.C.A), Calle 222#55-37, Bogotá 111166, Colombia; Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50#26-20, Bogotá 111321, Colombia; PhD Programme in Biotechnology, Faculty of Sciences, Universidad Nacional de Colombia, Carrera 45#26-85, Bogotá 111321, Colombia
| | - Carlos Parra-López
- Microbiology Department, Faculty of Medicine, Universidad Nacional de Colombia, Carrera 45#26-85, Bogotá 111321, Colombia.
| | - Manuel Alfonso Patarroyo
- Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50#26-20, Bogotá 111321, Colombia; Microbiology Department, Faculty of Medicine, Universidad Nacional de Colombia, Carrera 45#26-85, Bogotá 111321, Colombia.
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8
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Stieger A, Huber M, Yu Z, Kessler BM, Fischer R, Andereggen L, Kobel B, Stueber F, Luedi MM, Filipovic MG. Association of Indoleamine 2,3-Dioxygenase (IDO) Activity with Outcome after Cardiac Surgery in Adult Patients. Metabolites 2024; 14:334. [PMID: 38921469 PMCID: PMC11205801 DOI: 10.3390/metabo14060334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/05/2024] [Accepted: 06/10/2024] [Indexed: 06/27/2024] Open
Abstract
Indoleamine 2,3-deoxygenase (IDO) plays an important role in the catabolism of the amino acid tryptophan. Tryptophan and its metabolites are key immune modulators. Increased IDO activity has been observed in various diseases and is associated with worse clinical outcomes. However, comprehensive research regarding its role in cardiac surgery remains limited. Therefore, we aimed to investigate perioperative changes in IDO activity and pathway metabolites, along with their impact on clinical outcomes in adult patients undergoing cardiac surgery. As an observational cohort study conducted at the Inselspital in Bern from January to December 2019, we retrospectively analyzed the data of prospectively collected biobank samples of patients undergoing cardiac surgery with the use of cardiopulmonary bypass. IDO pathway metabolite analysis was conducted by mass spectrometry. Perioperative dynamics were descriptively assessed and associated with pre-defined clinical outcome measures (30-day mortality, 1-year mortality, incidence of stroke and myocardial infarction, and length of hospital stay) through a multi-step exploratory regression analysis. A cohort of 192 adult patients undergoing cardiac surgery with the use of cardiopulmonary bypass were included (median age 67.0, IQR 60.0-73.0, 75.5% male). A significant perioperative decrease in the kynurenine/tryptophan (Kyn/Trp) ratio (-2.298, 95% CI -4.028 to -596, p = 0.009) and significant perioperative dynamics in the associated metabolites was observed. No association of perioperative changes in IDO activity and pathway metabolites with clinical outcomes was found. A significant decrease in the Kyn/Trp ratio among adult patients undergoing cardiac surgery indicates a perioperative downregulation of IDO, which stands in contrast to other pro-inflammatory conditions. Further studies are needed to investigate IDO in the setting of perioperative immunomodulation, which is a key driver of postoperative complications in cardiac surgery patients.
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Affiliation(s)
- Andrea Stieger
- Department of Anaesthesiology and Pain Medicine, Cantonal Hospital of St. Gallen, 9007 St. Gallen, Switzerland;
| | - Markus Huber
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (M.H.); (B.K.); (F.S.); (M.G.F.)
| | - Zhanru Yu
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; (Z.Y.); (B.M.K.); (R.F.)
| | - Benedikt M. Kessler
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; (Z.Y.); (B.M.K.); (R.F.)
| | - Roman Fischer
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; (Z.Y.); (B.M.K.); (R.F.)
| | - Lukas Andereggen
- Department of Neurosurgery, Cantonal Hospital of Aarau, 5000 Aarau, Switzerland;
| | - Beatrice Kobel
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (M.H.); (B.K.); (F.S.); (M.G.F.)
| | - Frank Stueber
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (M.H.); (B.K.); (F.S.); (M.G.F.)
| | - Markus M. Luedi
- Department of Anaesthesiology and Pain Medicine, Cantonal Hospital of St. Gallen, 9007 St. Gallen, Switzerland;
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (M.H.); (B.K.); (F.S.); (M.G.F.)
| | - Mark G. Filipovic
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (M.H.); (B.K.); (F.S.); (M.G.F.)
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9
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Nicolini A, Rossi G, Ferrari P. Experimental and clinical evidence in favour of an effective immune stimulation in ER-positive, endocrine-dependent metastatic breast cancer. Front Immunol 2024; 14:1225175. [PMID: 38332913 PMCID: PMC10850262 DOI: 10.3389/fimmu.2023.1225175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 09/04/2023] [Indexed: 02/10/2024] Open
Abstract
In ER+ breast cancer, usually seen as the low immunogenic type, the main mechanisms favouring the immune response or tumour growth and immune evasion in the tumour microenvironment (TME) have been examined. The principal implications of targeting the oestrogen-mediated pathways were also considered. Recent experimental findings point out that anti-oestrogens contribute to the reversion of the immunosuppressive TME. Moreover, some preliminary clinical data with the hormone-immunotherapy association in a metastatic setting support the notion that the reversion of immune suppression in TME is likely favoured by the G0-G1 state induced by anti-oestrogens. Following immune stimulation, the reverted immune suppression allows the boosting of the effector cells of the innate and adaptive immune response. This suggests that ER+ breast cancer is a molecular subtype where a successful active immune manipulation can be attained. If this is confirmed by a prospective multicentre trial, which is expected in light of the provided evidence, the proposed hormone immunotherapy can also be tested in the adjuvant setting. Furthermore, the different rationale suggests a synergistic activity of our proposed immunotherapy with the currently recommended regimen consisting of antioestrogens combined with cyclin kinase inhibitors. Overall, this lays the foundation for a shift in clinical practice within this most prevalent molecular subtype of breast cancer.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Giuseppe Rossi
- Epidemiology and Biostatistics Unit, Institute of Clinical Physiology, National Research Council and Gabriele Monasterio Foundation, Pisa, Italy
| | - Paola Ferrari
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy
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10
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Ridnour LA, Cheng RYS, Heinz WF, Pore M, Gonzalez AL, Femino EL, Moffat R, Wink AL, Imtiaz F, Coutinho L, Butcher D, Edmondson EF, Rangel MC, Wong STC, Lipkowitz S, Glynn S, Vitek MP, McVicar DW, Li X, Anderson SK, Paolocci N, Hewitt SM, Ambs S, Billiar TR, Chang JC, Lockett SJ, Wink DA. Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.21.572867. [PMID: 38187660 PMCID: PMC10769421 DOI: 10.1101/2023.12.21.572867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER-breast cancers.
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Affiliation(s)
- Lisa A Ridnour
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
| | - Robert Y S Cheng
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
| | - William F Heinz
- Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research; Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD
| | - Milind Pore
- Imaging Mass Cytometry Frederick National Laboratory for Cancer Research
| | - Ana L Gonzalez
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
| | - Elise L Femino
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
| | - Rebecca Moffat
- Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research; Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD
| | - Adelaide L Wink
- Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research; Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD
| | - Fatima Imtiaz
- Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research; Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD
| | - Leandro Coutinho
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
- Faculdade de Medicina da Universidade de São Paulo and Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Donna Butcher
- Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for the National Cancer Institute
| | - Elijah F Edmondson
- Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for the National Cancer Institute
| | - M Cristina Rangel
- Faculdade de Medicina da Universidade de São Paulo and Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | | | - Sharon Glynn
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, University of Galway, Galway, Ireland
| | | | - Daniel W McVicar
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
| | - Xiaoxian Li
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA
| | - Stephen K Anderson
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
- Basic Science Program, Frederick National Laboratory for Cancer Research
| | - Nazareno Paolocci
- Division of Cardiology, Department of Medicine, Johns Hopkins University, and Department of Biomedical Sciences, University of Padova, Italy
- Laboratory of Pathology CCR, NCI, NIH
| | | | - Stefan Ambs
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Timothy R Billiar
- Mary and Ron Neal Cancer Center, Houston Methodist Hospital and Weill Cornell Medicine, Houston, TX
| | - Jenny C Chang
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
- Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research; Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD
- Imaging Mass Cytometry Frederick National Laboratory for Cancer Research
- Faculdade de Medicina da Universidade de São Paulo and Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, SP, Brazil
- Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for the National Cancer Institute
- Houston Methodist Weill Cornell Medical College, Houston TX
- Women's Malignancies Branch, CCR, NCI, NIH
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, University of Galway, Galway, Ireland
- (Mike Duke)
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA
- Basic Science Program, Frederick National Laboratory for Cancer Research
- Division of Cardiology, Department of Medicine, Johns Hopkins University, and Department of Biomedical Sciences, University of Padova, Italy
- Laboratory of Pathology CCR, NCI, NIH
- Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, MD
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
- Mary and Ron Neal Cancer Center, Houston Methodist Hospital and Weill Cornell Medicine, Houston, TX
| | - Stephen J Lockett
- Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research; Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD
| | - David A Wink
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
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11
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Pacheco JHL, Elizondo G. Interplay between Estrogen, Kynurenine, and AHR Pathways: An immunosuppressive axis with therapeutic potential for breast cancer treatment. Biochem Pharmacol 2023; 217:115804. [PMID: 37716620 DOI: 10.1016/j.bcp.2023.115804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 09/11/2023] [Accepted: 09/11/2023] [Indexed: 09/18/2023]
Abstract
Breast cancer is one of the most common malignancies among women worldwide. Estrogen exposure via endogenous and exogenous sources during a lifetime, together with environmental exposure to estrogenic compounds, represent the most significant risk factor for breast cancer development. As breast tumors establish, multiple pathways are deregulated. Among them is the aryl hydrocarbon receptor (AHR) signaling pathway. AHR, a ligand-activated transcription factor associated with the metabolism of polycyclic aromatic hydrocarbons and estrogens, is overexpressed in breast cancer. Furthermore, AHR and estrogen receptor (ER) cross-talk pathways have been observed. Additionally, the Tryptophan (Trp) catabolizing enzymes indolamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are overexpressed in breast cancer. IDO/TDO catalyzes the formation of Kynurenine (KYN) and other tryptophan-derived metabolites, which are ligands of AHR. Once KYN activates AHR, it stimulates the expression of the IDO enzyme, increases the level of KYN, and activates non-canonical pathways to control inflammation and immunosuppression in breast tumors. The interplay between E2, AHR, and IDO/TDO/KYN pathways and their impact on the immune system represents an immunosuppressive axis on breast cancer. The potential modulation of the immunosuppressive E2-AHR-IDO/TDO/KYN axis has aroused great expectations in oncotherapy. The present article will review the mechanisms implicated in generating the immunosuppressive axis E2-AHR-IDO/TDO/KYN in breast cancer and the current state of knowledge as a potential therapeutic target.
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Affiliation(s)
| | - Guillermo Elizondo
- Departamento de Biología Celular, CINVESTAV-IPN, Av. IPN 2508, C.P. 07360 Ciudad de México, México.
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12
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Moisand A, Madéry M, Boyer T, Domblides C, Blaye C, Larmonier N. Hormone Receptor Signaling and Breast Cancer Resistance to Anti-Tumor Immunity. Int J Mol Sci 2023; 24:15048. [PMID: 37894728 PMCID: PMC10606577 DOI: 10.3390/ijms242015048] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/02/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Breast cancers regroup many heterogeneous diseases unevenly responding to currently available therapies. Approximately 70-80% of breast cancers express hormone (estrogen or progesterone) receptors. Patients with these hormone-dependent breast malignancies benefit from therapies targeting endocrine pathways. Nevertheless, metastatic disease remains a major challenge despite available treatments, and relapses frequently ensue. By improving patient survival and quality of life, cancer immunotherapies have sparked considerable enthusiasm and hope in the last decade but have led to only limited success in breast cancers. In addition, only patients with hormone-independent breast cancers seem to benefit from these immune-based approaches. The present review examines and discusses the current literature related to the role of hormone receptor signaling (specifically, an estrogen receptor) and the impact of its modulation on the sensitivity of breast cancer cells to the effector mechanisms of anti-tumor immune responses and on the capability of breast cancers to escape from protective anti-cancer immunity. Future research prospects related to the possibility of promoting the efficacy of immune-based interventions using hormone therapy agents are considered.
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Affiliation(s)
- Alexandra Moisand
- CNRS UMR 5164, ImmunoConcEpT, Biological and Medical Sciences Department, University of Bordeaux, 33076 Bordeaux, France; (A.M.); (M.M.); (T.B.); (C.D.)
- Cancer Biology Graduate Program, UB Grad 2.0, University of Bordeaux, 33076 Bordeaux, France
| | - Mathilde Madéry
- CNRS UMR 5164, ImmunoConcEpT, Biological and Medical Sciences Department, University of Bordeaux, 33076 Bordeaux, France; (A.M.); (M.M.); (T.B.); (C.D.)
- Cancer Biology Graduate Program, UB Grad 2.0, University of Bordeaux, 33076 Bordeaux, France
| | - Thomas Boyer
- CNRS UMR 5164, ImmunoConcEpT, Biological and Medical Sciences Department, University of Bordeaux, 33076 Bordeaux, France; (A.M.); (M.M.); (T.B.); (C.D.)
- Cancer Biology Graduate Program, UB Grad 2.0, University of Bordeaux, 33076 Bordeaux, France
| | - Charlotte Domblides
- CNRS UMR 5164, ImmunoConcEpT, Biological and Medical Sciences Department, University of Bordeaux, 33076 Bordeaux, France; (A.M.); (M.M.); (T.B.); (C.D.)
- Department of Medical Oncology, University Hospital of Bordeaux, 33000 Bordeaux, France
| | - Céline Blaye
- CNRS UMR 5164, ImmunoConcEpT, Biological and Medical Sciences Department, University of Bordeaux, 33076 Bordeaux, France; (A.M.); (M.M.); (T.B.); (C.D.)
| | - Nicolas Larmonier
- CNRS UMR 5164, ImmunoConcEpT, Biological and Medical Sciences Department, University of Bordeaux, 33076 Bordeaux, France; (A.M.); (M.M.); (T.B.); (C.D.)
- Cancer Biology Graduate Program, UB Grad 2.0, University of Bordeaux, 33076 Bordeaux, France
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13
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Plaza-Diaz J, Álvarez-Mercado AI. The Interplay between Microbiota and Chemotherapy-Derived Metabolites in Breast Cancer. Metabolites 2023; 13:703. [PMID: 37367861 PMCID: PMC10301694 DOI: 10.3390/metabo13060703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/28/2023] Open
Abstract
The most common cancer in women is breast cancer, which is also the second leading cause of death in this group. It is, however, important to note that some women will develop or will not develop breast cancer regardless of whether certain known risk factors are present. On the other hand, certain compounds are produced by bacteria in the gut, such as short-chain fatty acids, secondary bile acids, and other metabolites that may be linked to breast cancer development and mediate the chemotherapy response. Modeling the microbiota through dietary intervention and identifying metabolites directly associated with breast cancer and its complications may be useful to identify actionable targets and improve the effect of antiangiogenic therapies. Metabolomics is therefore a complementary approach to metagenomics for this purpose. As a result of the combination of both techniques, a better understanding of molecular biology and oncogenesis can be obtained. This article reviews recent literature about the influence of bacterial metabolites and chemotherapy metabolites in breast cancer patients, as well as the influence of diet.
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Affiliation(s)
- Julio Plaza-Diaz
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain;
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
| | - Ana Isabel Álvarez-Mercado
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain;
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
- Institute of Nutrition and Food Technology, Biomedical Research Center, University of Granada, 18016 Armilla, Spain
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14
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Guo D, Wang Y, Wu X, Gao Y, Wang A, Zhang Z, Zhao K, Wang X, Liu M, Zhang Y, Li M, Chen R, Sun J, Zhang Y. Expression of Tryptophan Metabolism Enzymes in Patients with Diffuse Large B-cell Lymphoma and NK/T-cell Lymphoma. Cancer Med 2023. [PMID: 37148546 DOI: 10.1002/cam4.5903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/21/2023] [Accepted: 03/23/2023] [Indexed: 05/08/2023] Open
Abstract
BACKGROUND Metabolites of tryptophan (Trp) metabolism in the tumor microenvironment play crucial immunosuppressive roles in various cancers. However, the role of Trp metabolism in diffuse large B-cell lymphoma (DLBCL) or natural killer/T-cell lymphoma (NK/TCL) remains unelucidated. METHODS We investigated the potential role of Trp metabolism in a cohort of 43 patients with DLBCL and 23 with NK/TCL. We constructed tissue microarrays and performed in situ staining of Trp-catabolizing enzymes and PD-L1 using immunohistochemistry (IHC). RESULTS We observed 14.0% positive staining of IDO1 in DCBCL and 60.9% in NK/TCL; 55.8% of IDO2 in DCBCL and 95.7% in NK/TCL; 79.1% of TDO2 in DCBCL and 43.5% in NK/TCL; 29.7% of IL4I1 in DCBCL and 39.1% in NK/TCL. However, IDO1, IDO2, TDO2, and IL4I1 positivity did not significantly differ between PD-L1+ and PD-L1- biopsy tissue samples of NK/TCL; nonetheless, a positive correlation of IDO1 (r = 0.87, p < 0.001), IDO2 (r = 0.70, p < 0.001), TDO2 (r = 0.63, p < 0.001), and IL4I1 (r = 0.53, p < 0.05) with PD-L1 expression was observed in the TCGA-DLBCL dataset. Finally, immunohistochemical (IHC) analysis revealed the lack of superior prognostic effect with higher expression of Trp enzymes in DLBCL and NK/TCL. Furthermore, IDO1, IDO2, TDO2, and IL4I1 expression, as well as survival rates, did not significantly differ across all groups in the TCGA-DLBCL cohort. CONCLUSION Collectively, our findings provide novel insights into the enzymes involved in Trp metabolism in DLBCL and NK/TCL and their association with PD-L1 expression, which offers potential strategies to combine Trp-metabolism enzyme inhibitors with anti-PD-L1 or other immunotherapeutic strategies in clinical DLBCL or NK/TCL treatment.
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Affiliation(s)
- Dan Guo
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuming Wang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xunyao Wu
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yike Gao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anqi Wang
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zixin Zhang
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kun Zhao
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoxi Wang
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meiyu Liu
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yaran Zhang
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mei Li
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jian Sun
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Zhang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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15
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Noh BJ, Choi G, Jang H, Ma C, Oh HS, Kim M, Eom DW. Prognostic implications of immune classification using IDO1 expression in extrahepatic bile duct carcinoma. Oncol Lett 2022; 24:373. [PMID: 36238847 PMCID: PMC9494626 DOI: 10.3892/ol.2022.13493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/23/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Byeong-Joo Noh
- Department of Pathology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Gun Choi
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Hyuk Jang
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Chung Ma
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Ho-Suk Oh
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Moonho Kim
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Dae-Woon Eom
- Department of Pathology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
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16
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Alkhayyal N, Elemam NM, Hussein A, Magdub S, Jundi M, Maghazachi AA, Talaat IM, Bendardaf R. Expression of immune checkpoints (PD-L1 and IDO) and tumour-infiltrating lymphocytes in breast cancer. Heliyon 2022; 8:e10482. [PMID: 36097493 PMCID: PMC9463383 DOI: 10.1016/j.heliyon.2022.e10482] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 07/16/2022] [Accepted: 08/24/2022] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Breast cancer (BC) has become the most common cancer globally in 2020 as well as in the United Arab Emirates. The breast tumor microenvironment is composed of various immune cell types, including lymphocytes. Tumour-infiltrating lymphocytes (TILs) play a crucial role in tumor eradication and progression. Further, immune checkpoint markers such as programmed death receptor ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase (IDO) have been associated with tumor evasion from the immune system. In this study, we aimed to explore the status of TILs, PD-L1 and IDO as well as to investigate their association with the clinicopathological parameters. MATERIALS AND METHODS A total of 59 patients diagnosed with primary infiltrating BC were selected, after which tissue sections were stained to identify TILs along with immunohistochemical staining of PD-L1 and IDO. Moreover, in-silico tools were used to assess the expression of PD-L1, IDO and CD3ε in various molecular subtypes of BC. RESULTS It was found that the percentage of TILs correlated with estrogen receptor (ER) and progesterone receptor (PR) expression. This was supported by the finding that most of the triple-negative breast cancer (TNBC) cases belonged to the group with a high percentage of TILs (h-TILs). Similarly, the expression of PD-L1 and IDO was correlated with the ER and PR, whereas TNBC cases showed a high expression of PD-L1 and IDO. This goes in line with the in-silico findings where the TNBC group showed the highest expression of PD-L1 and IDO as well as the T cell marker CD3ε. CONCLUSION This study highlighted a possible link between the immunosuppressive markers PD-L1 and IDO with TILs density in the BC microenvironment.
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Affiliation(s)
- Noura Alkhayyal
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- University Hospital Sharjah, Sharjah, United Arab Emirates
| | - Noha M. Elemam
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Amal Hussein
- Department of Basic Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Sulaman Magdub
- Department of Pathology, Tawam Hospital, Alain, United Arab Emirates
| | - Majd Jundi
- University Hospital Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Iman M. Talaat
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Riyad Bendardaf
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- University Hospital Sharjah, Sharjah, United Arab Emirates
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17
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Feng Y, Ye Z, Song F, He Y, Liu J. The Role of TAMs in Tumor Microenvironment and New Research Progress. Stem Cells Int 2022; 2022:5775696. [PMID: 36004381 PMCID: PMC9395242 DOI: 10.1155/2022/5775696] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/24/2022] [Accepted: 07/28/2022] [Indexed: 02/08/2023] Open
Abstract
Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment (TME) and play a key role in TME, participating in the process of tumor occurrence, growth, invasion, and metastasis. Among them, metastasis to tumor tissue is the key step of malignant development of tumor. In this paper, the latest progress in the role of TAMs in the formation of tumor microenvironment is summarized. It is particularly noteworthy that cell and animal experiments show that TAMs can provide a favorable microenvironment for the occurrence and development of tumors. At the same time, clinical pathological experiments show that the accumulation of TAMs in tumor is related to poor clinical efficacy. Finally, this paper discusses the feasibility of TAMs-targeted therapy as a new indirect cancer therapy. This paper provides a theoretical basis for finding a potentially effective macrophage-targeted tumor therapy.
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Affiliation(s)
- Yawei Feng
- Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhiqiang Ye
- Department of Emergency, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Furong Song
- Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yufeng He
- Department of Intensive Care Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jun Liu
- Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
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18
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Dual-target inhibitors of indoleamine 2, 3 dioxygenase 1 (Ido1): A promising direction in cancer immunotherapy. Eur J Med Chem 2022; 238:114524. [PMID: 35696861 DOI: 10.1016/j.ejmech.2022.114524] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/08/2023]
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the kynurenine (Kyn) pathway of tryptophan metabolism in the first step, and the kynurenine pathway plays a fundamental role in immunosuppression in the tumor microenvironment. Therefore, researchers are vigorously developing IDO1 inhibitors, hoping to apply them to cancer immunotherapy. Nowadays, there have been 11 kinds of IDO1 inhibitors entering clinical trials, among which many inhibitors have shown good tumor inhibitory effect in phase I/II clinical trials. But the phase III study of the most promising IDO1 inhibitor compound 29 (Epacadostat) failed in 2018, which may be caused by the compensation effect offered by tryptophan 2,3-dioxygenase (TDO), the mismatched drug combination strategies, or other reasons. Luckily, dual-target inhibitors show great potential and advantages in solving these problems. In recent years, many studies have linked IDO1 to popular targets and selected many IDO1 dual-target inhibitors through pharmacophore fusion strategy and library construction, which enhance the tumor inhibitory effect and reduce side effects. Currently, three kinds of IDO1/TDO dual-target inhibitors have entered clinical trials, and extensive studies have been developing on IDO1 dual-target inhibitors. In this review, we summarize the IDO1 dual-target inhibitors developed in recent years and focus on the structure optimization process, structure-activity relationship, and the efficacy of in vitro and in vivo experiments, shedding a light on the pivotal significance of IDO1 dual-target inhibitors in the treatment of cancer, providing inspiration for the development of new IDO1 dual-target inhibitors.
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19
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Moragon S, Hernando C, Martinez-Martinez MT, Tapia M, Ortega-Morillo B, Lluch A, Bermejo B, Cejalvo JM. Immunological Landscape of HER-2 Positive Breast Cancer. Cancers (Basel) 2022; 14:3167. [PMID: 35804943 PMCID: PMC9265068 DOI: 10.3390/cancers14133167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
Understanding the biological aspects of immune response in HER2+ breast cancer is crucial to implementing new treatment strategies in these patients. It is well known that anti-HER2 therapy has improved survival in this population, yet a substantial percentage may relapse, creating a need within the scientific community to uncover resistance mechanisms and determine how to overcome them. This systematic review indicates the immunological mechanisms through which trastuzumab and other agents target cancer cells, also outlining the main trials studying immune checkpoint blockade. Finally, we report on anti-HER2 vaccines and include a figure exemplifying their mechanisms of action.
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Affiliation(s)
- Santiago Moragon
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (S.M.); (C.H.); (M.T.M.-M.); (M.T.); (B.O.-M.); (A.L.); (B.B.)
| | - Cristina Hernando
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (S.M.); (C.H.); (M.T.M.-M.); (M.T.); (B.O.-M.); (A.L.); (B.B.)
| | - Maria Teresa Martinez-Martinez
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (S.M.); (C.H.); (M.T.M.-M.); (M.T.); (B.O.-M.); (A.L.); (B.B.)
| | - Marta Tapia
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (S.M.); (C.H.); (M.T.M.-M.); (M.T.); (B.O.-M.); (A.L.); (B.B.)
| | - Belen Ortega-Morillo
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (S.M.); (C.H.); (M.T.M.-M.); (M.T.); (B.O.-M.); (A.L.); (B.B.)
| | - Ana Lluch
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (S.M.); (C.H.); (M.T.M.-M.); (M.T.); (B.O.-M.); (A.L.); (B.B.)
- Instituto de Salud Carlos III, CIBERONC (Centro De Investigacion Biomedica En Red De Cancer), 28220 Madrid, Spain
| | - Begoña Bermejo
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (S.M.); (C.H.); (M.T.M.-M.); (M.T.); (B.O.-M.); (A.L.); (B.B.)
- Instituto de Salud Carlos III, CIBERONC (Centro De Investigacion Biomedica En Red De Cancer), 28220 Madrid, Spain
| | - Juan Miguel Cejalvo
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain; (S.M.); (C.H.); (M.T.M.-M.); (M.T.); (B.O.-M.); (A.L.); (B.B.)
- Instituto de Salud Carlos III, CIBERONC (Centro De Investigacion Biomedica En Red De Cancer), 28220 Madrid, Spain
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20
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IDO1 plays a tumor-promoting role via MDM2-mediated suppression of the p53 pathway in diffuse large B-cell lymphoma. Cell Death Dis 2022; 13:572. [PMID: 35760783 PMCID: PMC9237101 DOI: 10.1038/s41419-022-05021-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 06/02/2022] [Accepted: 06/13/2022] [Indexed: 01/21/2023]
Abstract
With the intensive therapeutic strategies, diffuse large B-cell lymphoma (DLBCL) is still a fatal disease due to its progressive characteristics. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator that catalyzes the commitment step of the kynurenine pathway in the immune system, its aberrant activation may contribute to malignant cell escape eradication. However, the role of IDO1 in DLBCL progression remains elusive. Our study showed IDO1 expression was upregulated in DLBCL and was associated with a poor prognosis and low overall survival. Inhibition of IDO1 suppressed DLBCL cell proliferation in vitro and impeded xenograft tumorigenesis in vivo. RNA-seq analyses revealed MDM2 was downregulated while TP53 was upregulated in IDO1 inhibition OCI-Ly10 cells. Mechanistically, IDO1 inhibition decreased the expression of MDM2, a major negative regulator of p53, and restored p53 expression in OCI-Ly3 and OCI-Ly10 cells, resulting in cell cycle arrest and apoptosis. IDO1 inhibition induced cell apoptosis coupled with PUMA and BAX upregulation, as well as BCL2 and BCL-XL downregulation. In addition, p21, a p53 transcriptional target, was upregulated in cell cycle arrest. Taken together, this study revealed IDO1 is essential for the proliferation of DLBCL cells and may be a potential therapeutic target for the treatment of DLBCL.
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21
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Zhang R, Wang Y, Liu D, Luo Q, Du P, Zhang H, Wu W. Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice. Front Pharmacol 2022; 13:870848. [PMID: 35571116 PMCID: PMC9091350 DOI: 10.3389/fphar.2022.870848] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/28/2022] [Indexed: 02/05/2023] Open
Abstract
Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.
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Affiliation(s)
- Rongjie Zhang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Yuanfeiyi Wang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Dan Liu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Qing Luo
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China
| | - Peixin Du
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Haiyan Zhang
- Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, China.,The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Wenshuang Wu
- Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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22
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Essential amino acids deprivation is a potential strategy for breast cancer treatment. Breast 2022; 62:152-161. [PMID: 35217381 PMCID: PMC8873954 DOI: 10.1016/j.breast.2022.02.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 11/23/2022] Open
Abstract
Aims The study aimed to search novel, simple and practical index reflecting the level of essential amino acids (EAAs) metabolism in breast cancer (BC), as well as to explore the effect of enhanced EAAs metabolism on the prognosis and immune microenvironment of BC, thus providing new evidence for the application of EAAs deprivation in the BC treatment. Methods The study includes the analysis of multi-omics and clinical data of 13 BC cell lines and 2898 BC patients in the public database. Further validation was performed using multi-omics and immunohistochemistry data from 83 BC tissue samples collected at our hospital. Results According to the multi-omics data, the SLC7A5 to SLC7A8 Ratio (SSR) score was found to be significantly correlated with the EAAs level and EAAs-metabolic activity of BC, suggesting that the SSR score might be used as a biomarker to assess the degree of EAAs metabolism in BC. Besides, BC patients with high EAAs metabolism had shorter overall survival (OS) time, higher PD-L1 expression, and higher T regulatory cells (Tregs) infiltration, indicating that a high EAAs metabolism was related to a poor prognosis and immune suppression in BC. Additionally, MYC amplification is a critical molecular process in the metabolic reprogramming of EAAs in BC. Conclusion EAAs may be a possible therapeutic target for BC treatment.
A novel biomarker to assess the EAAs metabolism in breast cancer. High EAAs metabolism is related to a poor prognosis in breast cancer. High EAAs metabolism is also related to immune suppression in breast cancer. MYC amplification drives the metabolic reprogramming of EAAs in breast cancer.
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23
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Ikeda N, Kato D, Tsuboi M, Yoshitake R, Eto S, Yoshimoto S, Shinada M, Kamoto S, Hashimoto Y, Takahashi Y, Chambers J, Uchida K, Nishimura R, Nakagawa T. Detection of indoleamine 2,3-dioxygenase 1-expressing cells in canine normal and tumor tissues. J Vet Med Sci 2021; 83:1885-1890. [PMID: 34690223 PMCID: PMC8762412 DOI: 10.1292/jvms.21-0217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Cancer immunotherapy is a novel cancer treatment for canine tumors. Indoleamine
2,3-dioxygenase 1 (IDO1) is overexpressed in some human tumors and inhibits antitumor
immunity. In this study, we comprehensively evaluated expression pattern of IDO1 and the
nature of IDO1-expressing cells in canine normal and tumor tissues. In normal tissue
samples, IDO1 expression was detected only in the lymph nodes, spleen, tonsil tissues, and
colon tissues. In contrast, IDO1-positive tumor cells were observed in several tumor
tissue types. This is the first study to evaluate IDO1 expression in canine normal and
tumor tissues, and the results suggest that IDO1 is a promising target for novel cancer
immunotherapy in dogs with tumors.
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Affiliation(s)
- Namiko Ikeda
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Daiki Kato
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | | | - Ryohei Yoshitake
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Shotaro Eto
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Sho Yoshimoto
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Masahiro Shinada
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Satoshi Kamoto
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | | | | | - James Chambers
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Kazuyuki Uchida
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Ryohei Nishimura
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Takayuki Nakagawa
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo
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24
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Hashemzadeh N, Dolatkhah M, Aghanejad A, Barzegar-Jalali M, Omidi Y, Adibkia K, Barar J. Folate receptor-mediated delivery of 1-MDT-loaded mesoporous silica magnetic nanoparticles to target breast cancer cells. Nanomedicine (Lond) 2021; 16:2137-2154. [PMID: 34530630 DOI: 10.2217/nnm-2021-0176] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Aims: The efficiency of mesoporous silica magnetic nanoparticles (MSMNP) as a targeted drug-delivery system was investigated. Methods: The superparamagnetic iron oxide nanoparticles (NP) were synthesized, coated with mesoporous silica and conjugated with polyethylene glycol and methotrexate. Next, 1-methyl-D-tryptophan was loaded into the prepared nanosystems (NS). They were characterized using transmission electron microscopy, scanning electron microscopy, dynamic light scattering, vibrating sample magnetometer, x-ray powder diffraction, Fourier transform-infrared spectroscopy and the Brunauer-Emmett-Teller method and their biological impacts on breast cancer cells were evaluated. Results: The prepared NSs displayed suitable properties and showed enhanced internalization by folate-receptor-expressing cells, exerting efficient cytotoxicity, which was further enhanced by the near-infrared radiation irradiation. Conclusion: On the basis of our findings, the engineered NS is a promising multifunctional nanomedicine/theranostic for solid tumors.
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Affiliation(s)
- Nastaran Hashemzadeh
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 51656-65811, Iran.,Student Research Committee, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 516664-14766, Iran.,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 516664-14766, Iran
| | - Mitra Dolatkhah
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 51656-65811, Iran.,Student Research Committee, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 516664-14766, Iran.,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 516664-14766, Iran
| | - Ayuob Aghanejad
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 51656-65811, Iran
| | - Mohammad Barzegar-Jalali
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 516664-14766, Iran
| | - Yadollah Omidi
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Khosro Adibkia
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 51656-65811, Iran.,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 516664-14766, Iran
| | - Jaleh Barar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 51656-65811, Iran.,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 516664-14766, Iran
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25
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Asghar K, Farooq A, Zulfiqar B, Loya A. Review of 10 years of research on breast cancer patients: Focus on indoleamine 2,3-dioxygenase. World J Clin Oncol 2021; 12:429-436. [PMID: 34189067 PMCID: PMC8223715 DOI: 10.5306/wjco.v12.i6.429] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/30/2020] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
Therapeutic manipulation of the immune system in cancer has been an extensive area of research in the field of oncoimmunology. Immunosuppression regulates antitumour immune responses. An immunosuppressive enzyme, indoleamine 2,3-dioxygenase (IDO) mediates tumour immune escape in various malignancies including breast cancer. IDO upregulation in breast cancer cells may lead to the recruitment of regulatory T (T-regs) cells into the tumour microenvironment, thus inhibiting local immune responses and promoting metastasis. Immunosuppression induced by myeloid derived suppressor cells activated in an IDO-dependent manner may enhance the possibility of immune evasion in breast cancer. IDO overexpression has independent prognostic significance in a subtype of breast cancer of emerging interest, basal-like breast carcinoma. IDO inhibitors as adjuvant therapeutic agents may have clinical implications in breast cancer. This review proposes future prospects of IDO not only as a therapeutic target but also as a valuable prognostic marker for breast cancer.
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Affiliation(s)
- Kashif Asghar
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
| | - Asim Farooq
- Department of Clinical Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
| | - Bilal Zulfiqar
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia
| | - Asif Loya
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
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26
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Precision oncology for breast cancer through clinical trials. Clin Exp Metastasis 2021; 39:71-78. [PMID: 33950412 DOI: 10.1007/s10585-021-10092-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/22/2021] [Indexed: 12/26/2022]
Abstract
Precision treatment for breast cancers has made several notable advances in recent decades, but challenges of tumor heterogeneity, drug resistance, and aggressive recurrence and metastases remain. To meet and overcome these challenges, we must refine our understanding of breast subtypes and treatment biomarkers according to the knowledge afforded across the spectrum of 'omics assays. A critical aspect of harnessing this knowledge into actionable biomarkers for treatment decision relies on our ability to integrate knowledge across data types and leverage our insight in evidence-based clinical trials. We review recent advances in cutting-edge clinical trials for precision treatment of breast cancer, including chemotherapies, targeted therapies, immunotherapies, and combination therapies. We comment on promising future areas of development for this exciting point in precision breast cancer research.
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27
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Anurag M, Zhu M, Huang C, Vasaikar S, Wang J, Hoog J, Burugu S, Gao D, Suman V, Zhang XH, Zhang B, Nielsen T, Ellis MJ. Immune Checkpoint Profiles in Luminal B Breast Cancer (Alliance). J Natl Cancer Inst 2021; 112:737-746. [PMID: 31665365 DOI: 10.1093/jnci/djz213] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 09/12/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Unlike estrogen receptor (ER)-negative breast cancer, ER-positive breast cancer outcome is less influenced by lymphocyte content, indicating the presence of immune tolerance mechanisms that may be specific to this disease subset. METHODS A supervised analysis of microarray data from the ACOSOG Z1031 (Alliance) neoadjuvant aromatase inhibitor (AI) trial identified upregulated genes in Luminal (Lum) B breast cancers that correlated with AI-resistant tumor proliferation (percentage of Ki67-positive cancer nuclei, Pearson r > 0.4) (33 cases Ki67 > 10% on AI) vs LumB breast cancers that were more AI sensitive (33 cases Ki67 < 10% on AI). Overrepresentation analysis was performed using WebGestalt. All statistical tests were two-sided. RESULTS Thirty candidate genes positively correlated (r ≥ 0.4) with AI-resistant proliferation in LumB and were upregulated greater than twofold. Gene ontologies identified that the targetable immune checkpoint (IC) components IDO1, LAG3, and PD1 were overrepresented resistance candidates (P ≤ .001). High IDO1 mRNA was associated with poor prognosis in LumB disease (Molecular Taxonomy of Breast Cancer International Consortium, hazard ratio = 1.43, 95% confidence interval = 1.04 to 1.98, P = .03). IDO1 also statistically significantly correlated with STAT1 at protein level in LumB disease (Pearson r = 0.74). As a composite immune tolerance signature, expression of IFN-γ/STAT1 pathway components was associated with higher baseline Ki67, lower estrogen, and progesterone receptor mRNA levels and worse disease-specific survival (P = .002). In a tissue microarray analysis, IDO1 was observed in stromal cells and tumor-associated macrophages, with a higher incidence in LumB cases. Furthermore, IDO1 expression was associated with a macrophage mRNA signature (M1 by CIBERSORT Pearson r = 0.62 ) and by tissue microarray analysis. CONCLUSIONS Targetable IC components are upregulated in the majority of endocrine therapy-resistant LumB cases. Our findings provide rationale for IC inhibition in poor-outcome ER-positive breast cancer.
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MESH Headings
- Antigens, CD/biosynthesis
- Antigens, CD/genetics
- Antigens, CD/immunology
- Antineoplastic Agents, Hormonal/therapeutic use
- Aromatase Inhibitors/therapeutic use
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/immunology
- Cell Proliferation/physiology
- Drug Resistance, Neoplasm
- Female
- Humans
- Immune Tolerance
- Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis
- Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology
- Interferon-gamma/metabolism
- Letrozole/therapeutic use
- Prognosis
- Programmed Cell Death 1 Receptor/biosynthesis
- Programmed Cell Death 1 Receptor/genetics
- Programmed Cell Death 1 Receptor/immunology
- STAT1 Transcription Factor/metabolism
- Signal Transduction
- Tissue Array Analysis
- Transcriptome
- Up-Regulation
- Lymphocyte Activation Gene 3 Protein
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28
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Zhou Q, Cao FH, Liu H, Zuo MZ. Comprehensive analysis of the prognostic value and immune function of the IDO1 gene in gynecological cancers. Am J Transl Res 2021; 13:2041-2059. [PMID: 34017374 PMCID: PMC8129385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 12/11/2020] [Indexed: 06/12/2023]
Abstract
Gynecologic cancer is a serious global healthcare issue with high rates of mortality and morbidity. In recent years, tumor immunity and immunotherapy have attracted extensive attention for treatment of gynecological cancers. Indoleamine 2, 3-dioxygenase 1 (IDO1) plays a critical role in cancer immune escape, and its inhibition has been explored for immune-targeted therapies for many malignancies. However, knowledge about IDO1 involvement in the pathogenesis of gynecological cancers and its therapeutic potential is still evolving. In the current study, we integrated bioinformatics analysis of the prognostic value and immune function of IDO1 in gynecologic malignancies using Oncomine, GEPIA, HPA, TIMER, TISIDB, SurvExpress and Metascape database. Comprehensive analysis revealed that the transcription levels of IDO1 were significantly overexpressed in patients with gynecologic cancers, and IDO1-co-expressed gene signatures may be useful potential prognostic markers for gynecologic cancers. Furthermore, increased IDO1 expression correlated with immune infiltration cells, immune marker sets, and immunomodulators in gynecological cancers. These findings suggest that IDO1 plays an important role in immune infiltration and could potentially be an immunotherapeutic target for gynecological cancers. However, future large-scale and comprehensive research is required to validate our results.
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Affiliation(s)
- Quan Zhou
- Department of Gynecology and Obstetrics, The People’s Hospital of China Three Gorges University/The First People’s Hospital of YichangYichang 443000, Hubei, P. R. China
| | - Fan-Hua Cao
- Department of Nephrology, Traditional Chinese Medicine Hospital of China Three Gorges University/Yichang Hospital of Traditional Chinese MedicineYichang 443000, Hubei, China
| | - Hui Liu
- Department of Gynecology and Obstetrics, The People’s Hospital of China Three Gorges University/The First People’s Hospital of YichangYichang 443000, Hubei, P. R. China
| | - Man-Zhen Zuo
- Department of Gynecology and Obstetrics, The People’s Hospital of China Three Gorges University/The First People’s Hospital of YichangYichang 443000, Hubei, P. R. China
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29
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Liu J, Li Z, Zhao D, Feng X, Wang C, Li D, Ding J. Immunogenic cell death-inducing chemotherapeutic nanoformulations potentiate combination chemoimmunotherapy. MATERIALS & DESIGN 2021; 202:109465. [DOI: 10.1016/j.matdes.2021.109465] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/07/2024]
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ARG1 mRNA Level Is a Promising Prognostic Marker in Head and Neck Squamous Cell Carcinomas. Diagnostics (Basel) 2021; 11:diagnostics11040628. [PMID: 33807310 PMCID: PMC8065482 DOI: 10.3390/diagnostics11040628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/23/2021] [Accepted: 03/29/2021] [Indexed: 01/01/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCC) can be induced by smoking or alcohol consumption, but a growing part of cases relate to a persistent high-risk papillomavirus (HPV) infection. Viral etiology has a beneficial impact on the prognosis, which may be explained by a specific immune response. Tumor associated macrophages (TAMs) represent the main immune population of the tumor microenvironment with a controversial influence on the prognosis. In this study, the level, phenotype, and spatial distribution of TAMs were evaluated, and the expression of TAM-associated markers was compared in HPV positive (HPV+) and HPV negative (HPV−) tumors. Seventy-three formalin and embedded in paraffin (FFPE) tumor specimens were examined using multispectral immunohistochemistry for the detection of TAM subpopulations in the tumor parenchyma and stroma. Moreover, the mRNA expression of TAM markers was evaluated using RT-qPCR. Results were compared with respect to tumor etiology, and the prognostic significance was evaluated. In HPV− tumors, we observed more pro-tumorigenic M2 in the stroma and a non-macrophage arginase 1 (ARG1)-expressing population in both compartments. Moreover, higher mRNA expression of M2 markers—cluster of differentiation 163 (CD163), ARG1, and prostaglandin-endoperoxide synthase 2 (PTGS2)—was detected in HPV− patients, and of M1 marker nitric oxide synthase 2 (NOS2) in HPV+ group. The expression of ARG1 mRNA was revealed as a negative prognostic factor for overall survival of HNSCC patients.
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Mariotti V, Han H, Ismail-Khan R, Tang SC, Dillon P, Montero AJ, Poklepovic A, Melin S, Ibrahim NK, Kennedy E, Vahanian N, Link C, Tennant L, Schuster S, Smith C, Danciu O, Gilman P, Soliman H. Effect of Taxane Chemotherapy With or Without Indoximod in Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA Oncol 2021; 7:61-69. [PMID: 33151286 DOI: 10.1001/jamaoncol.2020.5572] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Importance Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial. Objective To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane. Design, Setting, and Participants This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020. Interventions A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. Main Outcomes and Measures The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and β = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis. Results Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms. Conclusions and Relevance This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. Trial Registration ClinicalTrials.gov Identifier: NCT01792050.
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Affiliation(s)
| | - Hyo Han
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | | | - Shou-Ching Tang
- University of Mississippi Cancer Center and Research Institute, Jackson
| | | | | | | | - Susan Melin
- Wake Forest University, Winston-Salem, North Carolina
| | | | | | | | | | | | | | | | | | - Paul Gilman
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
| | - Hatem Soliman
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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Arianfar E, Shahgordi S, Memarian A. Natural Killer Cell Defects in Breast Cancer: A Key Pathway for Tumor Evasion. Int Rev Immunol 2020; 40:197-216. [PMID: 33258393 DOI: 10.1080/08830185.2020.1845670] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
As the most important innate immune component cancers invader, natural killer (NK) cells have a magnificent role in antitumor immunity without any prior sensitization. Different subsets of NK cells have distinct responses during tumor cell exposure, according to their phenotypes and environments. Their function is induced mainly by the activity of both inhibitory and activating receptors against cancerous cells. Since the immunosuppression in the tumor microenvironment of breast cancer patients has directly deteriorated the phenotype and disturbed the function of NK cells, recruiting compensatory mechanisms indicate promising outcomes for immunotherapeutic approaches. These evidences accentuate the importance of NK cell distinct features in protection against breast tumors. In this review, we discuss the several mechanisms involved in NK cells suppression which consequently promote tumor progression and disease recurrence in patients with breast cancer.
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Affiliation(s)
- Elaheh Arianfar
- Student Research Committee, Faculty of Medicine, Department of Immunology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sanaz Shahgordi
- Student Research Committee, Faculty of Medicine, Department of Immunology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ali Memarian
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran.,Immunology department, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
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33
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Ebokaiwe AP, Njoya EM, Sheng Y, Zhang Z, Li S, Zhou Z, Qiang Z, Peng T, Hussein AA, Zhang G, Lu X, Li L, Wang F. Salinomycin promotes T-cell proliferation by inhibiting the expression and enzymatic activity of immunosuppressive indoleamine-2,3-dioxygenase in human breast cancer cells. Toxicol Appl Pharmacol 2020; 404:115203. [PMID: 32822738 DOI: 10.1016/j.taap.2020.115203] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 08/13/2020] [Accepted: 08/15/2020] [Indexed: 01/25/2023]
Abstract
Indoleamine 2,3 dioxygenase (IDO) is upregulated in many tumor types, including breast cancer, and plays a reputable role in promoting tumor immune tolerance. The importance of the immunosuppressive mechanism of IDO by suppressing T-cell function has garnered profound interest in the development of clinical IDO inhibitors. Herein, we established a screening method with cervical HeLa cells to induce IDO expression using interferon-γ (IFN-γ). After screening our chemical library, we found that salinomycin potently inhibited IFN-γ-stimulated kynurenine synthesis with IC50 values of 3.36-4.66 μM in both human cervical and breast cancer cells. Salinomycin lowered the IDO1 and IDO2 expression with no impact on the expression of tryptophan-2,3-dioxygenase. Interestingly, salinomycin potently repressed the IDO1 enzymatic activity by directly targeting the proteins in cells. Molecular docking revealed an alignment that favors nucleophilic attack of salinomycin in the catalytic domain of IDO1. Activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway by IFN-γ was significantly suppressed by salinomycin, via inhibiting the Jak1, Jak2, and STAT1/3 phosphorylation. Moreover, it inhibited IFN-γ-induced activation of the nuclear factor (NF)-κB pathway by inhibiting IκB degradation and NF-κB phosphorylation without affecting BIN1 expression. Furthermore, salinomycin significantly restored the proliferation of T cells co-cultured with IFN-γ-treated breast cancer cells and potentiated antitumor activity of cisplatin in vivo. These findings suggest that salinomycin suppresses kynurenine synthesis by inhibiting the catalytic activity of IDO1 and its expression by inhibiting the JAK/STAT and NF-κB pathways. Salinomycin warrants further investigation as a novel dual-functional IDO inhibitor for cancer immunotherapy.
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Affiliation(s)
- Azubuike Peter Ebokaiwe
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; Department of Chemistry/Biochemistry and Molecular Biology, Alex Ekwueme Federal University Ndufu Alike-, Ikwo, Nigeria
| | - Emmanuel Mfotie Njoya
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; Department of Biochemistry, Faculty of Science, University of Yaoundé I, P.O Box 812, Yaoundé, Cameroon
| | - Yuwen Sheng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Zhonghui Zhang
- College of Chemical Engineering, Sichuan University, Chengdu 610064, China
| | - Sheng Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Zongyuan Zhou
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Zhe Qiang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Ting Peng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Ahmed A Hussein
- Chemistry Department, Cape Peninsula University of Technology, Bellville Campus, Bellville 7537, Western Cape, South Africa
| | - Guolin Zhang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Xiaoxia Lu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Lin Li
- Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China.
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
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Meireson A, Devos M, Brochez L. IDO Expression in Cancer: Different Compartment, Different Functionality? Front Immunol 2020; 11:531491. [PMID: 33072086 PMCID: PMC7541907 DOI: 10.3389/fimmu.2020.531491] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.
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Affiliation(s)
- Annabel Meireson
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium
| | - Michael Devos
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium
| | - Lieve Brochez
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium
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35
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Loeser H, Kraemer M, Gebauer F, Bruns C, Schröder W, Zander T, Alakus H, Hoelscher A, Buettner R, Lohneis P, Quaas A. Indoleamine 2,3-Dioxygenase (IDO) Expression Is an Independent Prognostic Marker in Esophageal Adenocarcinoma. J Immunol Res 2020; 2020:2862647. [PMID: 33029538 PMCID: PMC7527882 DOI: 10.1155/2020/2862647] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 08/31/2020] [Accepted: 09/02/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Indoleamine 2,3-dioxygenase (IDO) is an interferon-inducible immune checkpoint expressed on tumor-infiltrating lymphocytes (TILs). IDO is known as a poor prognostic marker in esophageal squamous cell cancer, while a positive effect was shown for breast cancer. A comprehensive analysis of IDO expression in a well-defined cohort of esophageal adenocarcinoma (EAC) is missing. METHODS We analyzed 551 patients with EAC using single-protein and multiplex immunohistochemistry as well as mRNA in situ technology for the expression and distribution of IDO on subtypes of TILs (INF-γ mRNA and CD4- and CD8-positive T lymphocytes). RESULTS IDO expression on TILs was seen in up to 59.6% of tumors, and expression on tumor cells was seen in 9.2%. We found a strong positive correlation of IDO-positive TILs, CD3-positive T lymphocytes, and INF-γ mRNA-producing TILs in the tumor microenvironment of EACs showing significantly better overall survival (47.7 vs. 22.7 months, p < 0.001) with emphasis on early tumor stages (pT1/2: 142.1 vs. 37.1 months, p < 0.001). In multivariate analysis, IDO is identified as an independent prognostic marker. CONCLUSIONS Our study emphasizes the importance of immunomodulation in EAC marking IDO as a potential biomarker. Beyond this, IDO might indicate a subgroup of EAC with an explicit survival benefit.
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Affiliation(s)
- Heike Loeser
- Institute of Pathology, University Hospital Cologne, Germany
- Gastrointestinal Cancer Group Cologne, Department I for Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany
| | - Max Kraemer
- Institute of Pathology, University Hospital Cologne, Germany
| | - Florian Gebauer
- Gastrointestinal Cancer Group Cologne, Department I for Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Germany
| | - Christiane Bruns
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Germany
| | - Wolfgang Schröder
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Germany
| | - Thomas Zander
- Gastrointestinal Cancer Group Cologne, Department I for Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany
- Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital Cologne, Germany
| | - Hakan Alakus
- Gastrointestinal Cancer Group Cologne, Department I for Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Germany
| | - Arnulf Hoelscher
- Center for Esophageal and Gastric Surgery, AGAPLESION Markus Krankenhaus, Frankfurt, Germany
| | | | - Philipp Lohneis
- Institute of Pathology, University Hospital Cologne, Germany
- Gastrointestinal Cancer Group Cologne, Department I for Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Germany
- Gastrointestinal Cancer Group Cologne, Department I for Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany
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36
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Ben Yahia H, Boujelbene N, Babay W, Ben Safta I, Dhouioui S, Zemni I, Ali Ayadi M, Charfi L, Ouzari HI, Rebmann V, Rizzo R, Mrad K, Driss M, Zidi I. Expression analysis of immune-regulatory molecules HLA-G, HLA-E and IDO in endometrial cancer. Hum Immunol 2020; 81:305-313. [PMID: 32273131 DOI: 10.1016/j.humimm.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 03/01/2020] [Accepted: 03/26/2020] [Indexed: 11/17/2022]
Abstract
HLA-G has been widely implicated in advanced cancers through different pathways of immunosuppression allowing tumor escape. Contrarily, HLA-E has a controversial role in the tumor escape from the immune system. IDO catabolic enzyme is known to be up-regulated in many tumors types allowing their immune escape. Based on these considerations, we investigated the expression of HLA-G, HLA-E and IDO molecules in endometrial cancer (EC) and their association with prognostic clinicopathologic parameters. Their expression were checked in tumoral and adjacent endometrial tissues. Both HLA-G and IDO immunostaining were significantly increased in EC tissues compared to normal residual endometrial glands (Mann Whitney U-test, p = 0.0001 and p = 0,020 respectively). However, HLA-E was highly expressed in tumoral tissues as well as in normal residual endometrial glands (respectively, 100% and 81.8%). Increased HLA-G expression levels were observed in high histological grade (grade 3), and in the non-endometrioid type 2 EC. Unexpectedly, patients with IDO Low expression had significantly impaired overall survival compared to patients with IDO High (log-rank p = 0.021). Conversely, HLA-E low expression was associated to an improved overall survival EC (log-rank p = 0.004). We concluded that, HLA-G and IDO are highly expressed in EC compared to adjacent normal endometrial tissues, that might be interesting for the EC outcome.
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Affiliation(s)
- Hamza Ben Yahia
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nadia Boujelbene
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia; Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Wafa Babay
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Inès Ben Safta
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Sabrine Dhouioui
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Inès Zemni
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Mohamed Ali Ayadi
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Lamia Charfi
- Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Hadda Imene Ouzari
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, Virchowstr. 179, 45147 Essen, Germany
| | - Roberta Rizzo
- Department of Experimental and Diagnostic Medicine, Section Microbiology, University of Ferrara, Ferrara, Italy
| | - Karima Mrad
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia; Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Maha Driss
- Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Inès Zidi
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia.
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37
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Humphries MP, Craig SG, Kacprzyk R, Fisher NC, Bingham V, McQuaid S, Murray GI, McManus D, Turkington RC, James J, Salto-Tellez M. The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation. BMC Cancer 2020; 20:500. [PMID: 32487090 PMCID: PMC7268770 DOI: 10.1186/s12885-020-06987-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification. METHODS Three hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density. RESULTS CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223-0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363-0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS. CONCLUSIONS Multiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification.
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Affiliation(s)
- Matthew P Humphries
- Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | - Stephanie G Craig
- Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | - Rafal Kacprzyk
- Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | - Natalie C Fisher
- Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | - Victoria Bingham
- Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | - Stephen McQuaid
- Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast, UK
- Northern Ireland Biobank, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK
| | - Graeme I Murray
- Pathology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, Scotland
| | - Damian McManus
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast, UK
| | | | - Jacqueline James
- Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast, UK
- Northern Ireland Biobank, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK
| | - Manuel Salto-Tellez
- Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK.
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast, UK.
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Differential Expression and Clinicopathological Significance of HER2, Indoleamine 2,3-Dioxygenase and PD-L1 in Urothelial Carcinoma of the Bladder. J Clin Med 2020; 9:jcm9051265. [PMID: 32349330 PMCID: PMC7288001 DOI: 10.3390/jcm9051265] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/17/2020] [Accepted: 04/24/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose: Evasion of the immune system by cancer cells allows for the progression of tumors. Antitumor immunotherapy has shown remarkable effects in a diverse range of cancers. The aim of this study was to determine the clinicopathological significance of human epidermal growth factor receptor 2 (HER2), indoleamine 2,3-dioxygenase (IDO), and programmed death ligand-1 (PD-L1) expression in urothelial carcinoma of the bladder (UCB). Materials and Methods: We retrospectively studied 97 patients with UCB. We performed an immunohistochemical study to measure the expression levels of HER2, IDO, and PD-L1 in UCB tissue from these 97 patients. Results: In all 97 cases, the PD-L1 expression of tumor-infiltrating immune cells (ICs) was significantly correlated with higher pathologic tumor stage (pT). In pT2–pT4 cases (n = 69), higher levels of HER2 and IDO expression in invasive tumor cells (TCs) were associated with shorter periods of disease-free survival (DFS). Conclusion: These results imply that the expression of PD-L1 in ICs of the UCB microenvironment is associated with cancer invasion and the expression of HER2 or IDO in the invasive cancer cell and suggestive of the potential for cancer recurrence. We suggest that the expression levels of IDO, HER2, and PD-L1 could be useful as targets in the development of combined cancer immunotherapeutic strategies.
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Chen B, Alvarado DM, Iticovici M, Kau NS, Park H, Parikh PJ, Thotala D, Ciorba MA. Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer. Cancer Immunol Res 2020; 8:451-464. [PMID: 32127391 PMCID: PMC7123802 DOI: 10.1158/2326-6066.cir-19-0282] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 11/08/2019] [Accepted: 02/20/2020] [Indexed: 12/13/2022]
Abstract
Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side effects. These data demonstrated that IDO1 inhibition potentiates radiotherapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Cell Line, Tumor
- Colorectal Neoplasms/enzymology
- Colorectal Neoplasms/immunology
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/radiotherapy
- Female
- Gene Expression Regulation, Enzymologic/drug effects
- Humans
- Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
- Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Interferons/pharmacology
- Intestinal Mucosa/radiation effects
- Kynurenine/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Oximes/pharmacology
- Radiation Tolerance/drug effects
- Radiation-Protective Agents/pharmacology
- Sulfonamides/pharmacology
- Tumor Microenvironment
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Affiliation(s)
- Baosheng Chen
- Inflammatory Bowel Diseases Center and the Division of Gastroenterology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri.
| | - David M Alvarado
- Inflammatory Bowel Diseases Center and the Division of Gastroenterology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri
| | - Micah Iticovici
- Inflammatory Bowel Diseases Center and the Division of Gastroenterology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri
| | - Nathan S Kau
- Inflammatory Bowel Diseases Center and the Division of Gastroenterology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri
| | - Haeseong Park
- Division of Medical Oncology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri
| | - Parag J Parikh
- Department of Radiation Oncology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri
| | - Dinesh Thotala
- Department of Radiation Oncology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri
| | - Matthew A Ciorba
- Inflammatory Bowel Diseases Center and the Division of Gastroenterology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri.
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40
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Costa RLB, Czerniecki BJ. Clinical development of immunotherapies for HER2 + breast cancer: a review of HER2-directed monoclonal antibodies and beyond. NPJ Breast Cancer 2020; 6:10. [PMID: 32195333 PMCID: PMC7067811 DOI: 10.1038/s41523-020-0153-3] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 02/18/2020] [Indexed: 02/07/2023] Open
Abstract
Human epidermal growth factor receptor 2-positive (HER2+) breast cancer accounts for ~25% of breast cancer cases. Monoclonal antibodies (mAbs) against HER2 have led to unparalleled clinical benefit for a subset of patients with HER2+ breast cancer. In this narrative review, we summarize advances in the understanding of immune system interactions, examine clinical developments, and suggest rationales for future investigation of immunotherapies for HER2+ breast cancer. Complex interactions have been found between different branches of the immune system, HER2+ breast cancer, and targeted treatments (approved and under investigation). A new wave of immunotherapies, such as novel HER2-directed mAbs, antibody drug conjugates, vaccines, and adoptive T-cell therapies, are being studied in a broad population of patients with HER2-expressing tumors. The development of immunotherapies for HER2+ breast cancer represents an evolving field that should take into account interactions between different components of the immune system.
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Affiliation(s)
- Ricardo L B Costa
- Departments of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL USA
| | - Brian J Czerniecki
- Departments of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL USA
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41
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Lanser L, Kink P, Egger EM, Willenbacher W, Fuchs D, Weiss G, Kurz K. Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer. Front Immunol 2020; 11:249. [PMID: 32153576 PMCID: PMC7047328 DOI: 10.3389/fimmu.2020.00249] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 01/30/2020] [Indexed: 12/13/2022] Open
Abstract
Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.
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Affiliation(s)
- Lukas Lanser
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Patricia Kink
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Eva Maria Egger
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Wolfgang Willenbacher
- Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria
- Oncotyrol Centre for Personalized Cancer Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Guenter Weiss
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Katharina Kurz
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
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42
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Zhao Y, Wei L, Liu J, Li F. Chemoresistance was correlated with elevated expression and activity of indoleamine 2,3-dioxygenase in breast cancer. Cancer Chemother Pharmacol 2019; 85:77-93. [PMID: 31844921 DOI: 10.1007/s00280-019-04009-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 12/04/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Indoleamine 2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan leading to the production of immunosuppressive kynurenine and tryptophan exhausting. IDO expression and activity contribute to aggressive tumor growth, inferior therapeutic gain and poor prognosis. The aim of this study was to explore the association between chemoresistance and IDO expression, activity in breast cancer METHODS: Immunohistochemistry was applied for evaluating IDO expression in biopsy tissues. Serum IDO activity was examined via High-performance liquid chromatography (HPLC). Western blots (WB), HPLC and Real-time PCR (RT-PCR) were used to analyze IDO protein, IDO enzyme activity and IDO gene expression in original and paclitaxel-resistant cells respectively. Logistic regression and survival analysis were applied to explore the association between chemoresistance and IDO expression, activity in breast cancer. RESULTS IDO expression in tumor tissues was associated with serum IDO activity (P = 0.004). Both IDO expression in tumor and serum activity were associated with clinical tumor stage, node stage and estrogen receptor (ER) status (all P < 0.05); clinical response and pathologic complete response (pCR) to NAC were both related to IDO expression and activity prior NAC (all P < 0.05). Multivariate analysis showed IDO activity before NAC was the only independent factor affected pCR (P = 0.032). ROC curves showed that the IDO expression and activity had discriminative ability for predicting the clinical response and pCR. In the prognostic analysis, patients with high IDO expression had significantly impaired overall survival (5 year survival rate: 53.57% vs 80.00%) and progression-free survival (5 year survival rate: 46.43% vs 72.00%, P = 0.031 and P = 0.046). In vitro, significantly increased IDO protein, IDO mRNA expression and IDO enzyme activity in paclitaxel-resistant cells were demonstrated in comparing of sensitive cells. CONCLUSION IDO expression and activity associated with advanced breast cancer, poor response to neoadjuvant chemotherapy and prognosis. IDO expression and activity were significantly increased in paclitaxel-resistant breast cancer cells.
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Affiliation(s)
- Yang Zhao
- The Second Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Breast Surgery, Cangzhou People's Hospital, Cangzhou, 061000, Hebei, China
| | - Lijuan Wei
- Department of Cancer Prevention Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China
| | - Juntian Liu
- The Second Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Cancer Prevention Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China
| | - Fangxuan Li
- Department of Cancer Prevention Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.
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43
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Adu-Gyamfi CG, Savulescu D, George JA, Suchard MS. Indoleamine 2, 3-Dioxygenase-Mediated Tryptophan Catabolism: A Leading Star or Supporting Act in the Tuberculosis and HIV Pas-de-Deux? Front Cell Infect Microbiol 2019; 9:372. [PMID: 31737575 PMCID: PMC6828849 DOI: 10.3389/fcimb.2019.00372] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 10/14/2019] [Indexed: 12/11/2022] Open
Abstract
Progression from latency to active Tuberculosis (TB) disease is mediated by incompletely understood host immune factors. The definitive characteristic of progressive human immunodeficiency virus (HIV) disease is a severe loss in number and function of T lymphocytes. Among the many possible mediators of T lymphocyte loss and ineffective function is the activity of the immune-modulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO is the rate-limiting enzyme converting tryptophan to kynurenine. IDO activity was initially recognized to mediate tolerance at the foeto-maternal interface. Recently, IDO activity has also been noted to play a critical role in immune tolerance to pathogens. Studies of host immune and metabolic mediators have found IDO activity significantly elevated in HIV and TB disease. In this review, we explore the link between IDO-mediated tryptophan catabolism and the presence of active TB disease in HIV-infected patients. We draw attention to increased IDO activity as a key factor marking the progression from latent to active TB disease in HIV-infected patients.
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Affiliation(s)
- Clement Gascua Adu-Gyamfi
- Centre for Vaccines and Immunology, National Institute for Communicable Diseases, Johannesburg, South Africa.,Department of Chemical Pathology, Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
| | - Dana Savulescu
- Centre for Vaccines and Immunology, National Institute for Communicable Diseases, Johannesburg, South Africa
| | - Jaya Anna George
- Department of Chemical Pathology, Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
| | - Melinda Shelley Suchard
- Centre for Vaccines and Immunology, National Institute for Communicable Diseases, Johannesburg, South Africa.,Department of Chemical Pathology, Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
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44
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Barriga V, Kuol N, Nurgali K, Apostolopoulos V. The Complex Interaction between the Tumor Micro-Environment and Immune Checkpoints in Breast Cancer. Cancers (Basel) 2019; 11:cancers11081205. [PMID: 31430935 PMCID: PMC6721629 DOI: 10.3390/cancers11081205] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 08/08/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023] Open
Abstract
The progression of breast cancer and its association with clinical outcome and treatment remain largely unexplored. Accumulating data has highlighted the interaction between cells of the immune system and the tumor microenvironment in cancer progression, and although studies have identified multiple facets of cancer progression within the development of the tumor microenvironment (TME) and its constituents, there is lack of research into the associations between breast cancer subtype and staging. Current literature has provided insight into the cells and pathways associated with breast cancer progression through expression analysis. However, there is lack of co-expression studies between immune pathways and cells of the TME that form pro-tumorigenic relationships contributing to immune-evasion. We focus on the immune checkpoint and TME elements that influence cancer progression, particularly studies in molecular subtypes of breast cancer.
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Affiliation(s)
- Vanessa Barriga
- College of Health and Biomedicine, Victoria University, Melbourne 3030, Australia
- Institute for Health and Sport, Victoria University, Melbourne 3030, Australia
| | - Nyanbol Kuol
- Institute for Health and Sport, Victoria University, Melbourne 3030, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Melbourne 3030, Australia
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45
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Onesti CE, Boemer F, Josse C, Leduc S, Bours V, Jerusalem G. Tryptophan catabolism increases in breast cancer patients compared to healthy controls without affecting the cancer outcome or response to chemotherapy. J Transl Med 2019; 17:239. [PMID: 31337401 PMCID: PMC6652004 DOI: 10.1186/s12967-019-1984-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/17/2019] [Indexed: 12/14/2022] Open
Abstract
Background Indoleamine 2,3-dioxygenase catalyzes the conversion of tryptophan to kynurenine, an immunosuppressive metabolite involved in T regulatory cell differentiation. Indoleamine 2,3-dioxygenase is expressed in many cancer types, including breast cancer. Here, we analyze kynurenine and tryptophan and their ratio in breast cancer patients and healthy controls. Methods Breast cancer patients and healthy controls were prospectively enrolled in our study. All subjects underwent blood sample withdrawal at diagnosis or on the day of screening mammography for the healthy controls. Plasmatic kynurenine and tryptophan were determined on a TQ5500 tandem mass spectrometer after chromatographic separation. Results We enrolled 146 healthy controls and 202 women with stages I–III breast cancer of all subtypes. All patients underwent surgery, 126 underwent neoadjuvant chemotherapy with 43 showing a pathological complete response, and 43 underwent adjuvant chemotherapy. We observed significantly higher plasmatic kynurenine, tryptophan and their ratio for the healthy controls compared to patients with breast cancer. We observed a lower plasmatic tryptophan and a higher kynurenine/tryptophan ratio in hormone receptor-negative patients compared to hormone receptor-positive cancers. Lobular cancers showed a lower ratio than any other histologies. Advanced cancers were associated with a lower tryptophan level and higher grades with an increased kynurenine/tryptophan ratio. Pathological complete response was associated with higher kynurenine values. The plasmatic kynurenine, tryptophan and kynurenine/tryptophan ratios were not predictive of survival. Conclusions The plasmatic kynurenine, tryptophan and kynurenine/tryptophan ratio could differentiate breast cancer patients from healthy controls. The Kyn/Trp ratio and Trp also showed different values according to hormone receptor status, TNM stage, T grade and histology. These results suggest a rapid metabolism in breast cancer, but no associations with outcome or sensitivity to chemotherapy were observed. Electronic supplementary material The online version of this article (10.1186/s12967-019-1984-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Concetta Elisa Onesti
- Medical Oncology Department, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium.,Laboratory of Human Genetics, GIGA Research Institute, Liège, Belgium
| | - François Boemer
- Department of Human Genetics, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium
| | - Claire Josse
- Medical Oncology Department, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium. .,Laboratory of Human Genetics, GIGA Research Institute, Liège, Belgium.
| | - Stephane Leduc
- Department of Human Genetics, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium
| | - Vincent Bours
- Laboratory of Human Genetics, GIGA Research Institute, Liège, Belgium.,Department of Human Genetics, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium
| | - Guy Jerusalem
- Medical Oncology Department, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium.,Liège University, Liège, Belgium
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46
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Zhang J, Pang Y, Xie T, Zhu L. CXCR4 antagonism in combination with IDO1 inhibition weakens immune suppression and inhibits tumor growth in mouse breast cancer bone metastases. Onco Targets Ther 2019; 12:4985-4992. [PMID: 31388305 PMCID: PMC6607200 DOI: 10.2147/ott.s200643] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 05/13/2019] [Indexed: 12/22/2022] Open
Abstract
Purpose To investigate whether inhibition of the CXCL12/CXCR4 axis or IDO1 could produce antitumor effects in a metastasized breast cancer immunocompetent animal model. Methods Breast cancer metastasis models were established in mice. CXCR4 inhibitor and IDO1 inhibitor were used to evaluate the anticancer effects. Results Combination treatment using the CXCR4 antagonist AMD3465 and the IDO1 inhibitor D1MT successfully delayed the progression of breast cancer bone metastases. AMD3465 reduced the number of intratumoral regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs), while D1MT facilitated the antitumor effects of intratumoral CD8+ T-cells. IDO1 inhibition elevated the expression of perforin, granzyme-B, and IFN-γ in CD8+ T-cells, and AMD3465 treatment weakened the potential immune suppressive effects of Tregs and MDSCs. As a result, combination treatment significantly prolonged tumor-bearing mouse survival in two metastasis models, and these antitumor effects relied on overexpression of indoleamine 2, 3-dioxygenase 1 (IDO1), an enzyme that modulates the immune response and impairs immune attack in ovarian cancers CXCR3+ CD8+ cytotoxic T-cell function. Conclusion The current study provides preclinical evidence that AMD3465 treatment in combination with IDO1 inhibition may be a promising therapeutic regimen for refractory metastasized breast cancers.
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Affiliation(s)
- Jian Zhang
- Department of Orthopaedics, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People's Republic of China
| | - Yanxia Pang
- Taizhou University Medical School , Linhai 318000, People's Republic of China
| | - Tao Xie
- Department of Orthopaedics, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People's Republic of China
| | - Liulong Zhu
- Department of Orthopaedics, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People's Republic of China
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47
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Kiyozumi Y, Baba Y, Okadome K, Yagi T, Ogata Y, Eto K, Hiyoshi Y, Ishimoto T, Iwatsuki M, Iwagami S, Miyamoto Y, Yoshida N, Watanabe M, Baba H. Indoleamine 2, 3-dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer. Cancer Sci 2019; 110:1863-1871. [PMID: 31012515 PMCID: PMC6549929 DOI: 10.1111/cas.14028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 04/18/2019] [Accepted: 04/19/2019] [Indexed: 02/06/2023] Open
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a primary enzyme that generates immunosuppressive metabolites. It plays a major role in tumor immunology and is a potential immune-based therapeutic target. We have reported that IDO1 protein expression was associated with an unfavorable clinical outcome in esophageal cancer. Recently, it has been reported that IDO1 expression is regulated by methylation of the IDO1 promoter. Thus, the aim of this study was to examine the relationship between IDO1 expression, IDO1 promoter methylation, and clinicopathological features in esophageal cancer. We first confirmed changes in IDO1 expression levels in vitro by treating cells with 5-azacytidine. We then evaluated the relationship between IDO1 expression levels, IDO1 promoter methylation (bisulfite pyrosequencing), and clinicopathological features using 40 frozen samples and 242 formalin-fixed, paraffin-embedded samples resected from esophageal cancer patients. We treated cell lines with 5-azacytidine, and the resulting hypomethylation induced significantly higher IDO1 expression (P < .001). In frozen samples, IDO1 expression levels correlated inversely with IDO1 promoter methylation levels (R = -0.47, P = .0019). Furthermore, patients in the IDO1 promoter hypomethylation group (n = 67) had a poor prognosis compared with those in the IDO1 promoter hypermethylation group (n = 175) (overall survival, P = .011). Our results showed that IDO1 promoter hypomethylation regulated IDO1 expression and was associated with a poor prognosis in esophageal cancer patients.
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Affiliation(s)
- Yuki Kiyozumi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kazuo Okadome
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Taisuke Yagi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoko Ogata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kojiro Eto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yukiharu Hiyoshi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Division of Translational Research and Advanced Treatment Against Gastrointestinal Cancer, Kumamoto University, Kumamoto, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shiro Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Division of Translational Research and Advanced Treatment Against Gastrointestinal Cancer, Kumamoto University, Kumamoto, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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Chrétien S, Zerdes I, Bergh J, Matikas A, Foukakis T. Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy. Cancers (Basel) 2019; 11:E628. [PMID: 31060337 PMCID: PMC6562626 DOI: 10.3390/cancers11050628] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 12/14/2022] Open
Abstract
Cancer immunotherapy has altered the management of human malignancies, improving outcomes in an expanding list of diseases. Breast cancer - presumably due to its perceived low immunogenicity - is a late addition to this list. Furthermore, most of the focus has been on the triple negative subtype because of its higher tumor mutational load and lymphocyte-enriched stroma, although emerging data show promise on the other breast cancer subtypes as well. To this point the clinical use of immunotherapy is limited to the inhibition of two immune checkpoints, Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Consistent with the complexity of the regulation of the tumor - host interactions and their lack of reliance on a single regulatory pathway, combinatory approaches have shown improved efficacy albeit at the cost of increased toxicity. Beyond those two checkpoints though, a large number of co-stimulatory or co-inhibitory molecules play major roles on tumor evasion from immunosurveillance. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials. The biological role, prognostic and predictive implications regarding breast cancer and early clinical efforts on exploiting these immune-related therapeutic targets are herein reviewed.
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Affiliation(s)
- Sebastian Chrétien
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
| | - Ioannis Zerdes
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
| | - Jonas Bergh
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
| | - Alexios Matikas
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
| | - Theodoros Foukakis
- Department of Oncology - Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden.
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Asghar K, Loya A, Rana IA, Tahseen M, Ishaq M, Farooq A, Bakar MA, Masood I. Indoleamine 2,3-dioxygenase expression and overall survival in patients diagnosed with breast cancer in Pakistan. Cancer Manag Res 2019; 11:475-481. [PMID: 30655699 PMCID: PMC6322492 DOI: 10.2147/cmar.s184221] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background 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. Materials and methods 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. Results 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. Conclusion 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.
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Affiliation(s)
- Kashif Asghar
- Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan,
| | - Asif Loya
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
| | - Iftikhar Ali Rana
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
| | - Muhammad Tahseen
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
| | - Muhammad Ishaq
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
| | - Asim Farooq
- Department of Biomedical Engineering & Sciences, School of Mechanical & Manufacturing Engineering, National University of Sciences & Technology (NUST), Islamabad, Pakistan
| | - Muhammad Abu Bakar
- Department of Cancer Registry and Clinical Data Management, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
| | - Iqra Masood
- Department of Clinical Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
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Lu J, Liu X, Liao YP, Wang X, Ahmed A, Jiang W, Ji Y, Meng H, Nel AE. Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway. ACS NANO 2018; 12:11041-11061. [PMID: 30481959 PMCID: PMC6262474 DOI: 10.1021/acsnano.8b05189] [Citation(s) in RCA: 177] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX). Intravenous injection of the encapsulated two-drug combination dramatically improved the pharmacokinetics and tumor drug concentrations of DOX and IND in an orthotopic 4T1 tumor model in syngeneic mice. Delivery of a threshold ICD stimulus resulted in the uptake of dying BC cells by dendritic cells, tumor antigen presentation and the activation/recruitment of naı̈ve T-cells. The subsequent activation of perforin- and IFN-γ releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. Immune phenotyping of the tumor tissues confirmed the recruitment of CD8+ cytotoxic T lymphocytes (CTLs), disappearance of Tregs, and an increase in CD8+/FOXP3+ T-cell ratios. Not only does the DOX/IND-Liposome provide a synergistic antitumor response that is superior to a DOX-only liposome, but it also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. All considered, an innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies.
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MESH Headings
- Animals
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Breast Neoplasms/immunology
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Cell Death/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Doxorubicin/administration & dosage
- Doxorubicin/chemistry
- Doxorubicin/pharmacology
- Drug Delivery Systems
- Drug Screening Assays, Antitumor
- Female
- Immunotherapy
- Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Liposomes/chemistry
- Mammary Neoplasms, Experimental/immunology
- Mammary Neoplasms, Experimental/pathology
- Mammary Neoplasms, Experimental/therapy
- Mice
- Mice, Inbred BALB C
- Tryptophan/administration & dosage
- Tryptophan/analogs & derivatives
- Tryptophan/chemistry
- Tryptophan/pharmacology
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Affiliation(s)
- Jianqin Lu
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
| | - Xiangsheng Liu
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
| | - Yu-Pei Liao
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
| | - Xiang Wang
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
| | - Ayman Ahmed
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
| | - Wen Jiang
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
| | - Ying Ji
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
| | - Huan Meng
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
- Phone: 310.825.0217. E-mail:
| | - Andre E. Nel
- Division
of NanoMedicine, Department of Medicine, David Geffen School
of Medicine, Center for Environmental Implications of Nanotechnology, California
NanoSystems Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California 90095, United States
- Phone: 310.825.6620. E-mail:
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