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Monsen P, Bommi PV, Grigorescu AA, Lauing KL, Mao Y, Berardi P, Zhai L, Ojo O, Penco-Campillo M, Koch T, Egozi M, Jha S, Dunne SF, Jiang H, Song G, Zhang F, Kregel S, Vaziri-Gohar A, Fanning SW, Sanchez-Gomez P, Allen JM, Yamini B, Lukas RV, Wainwright DA, Schiltz GE. Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC). J Med Chem 2025; 68:4961-4987. [PMID: 39946350 PMCID: PMC11874035 DOI: 10.1021/acs.jmedchem.5c00026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 02/06/2025] [Accepted: 02/10/2025] [Indexed: 02/19/2025]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and nonenzymatic functions. Drugs targeting IDO1 enzyme activity have failed to improve the overall survival of patients with cancer. Developing new therapeutics that neutralize both enzyme- and nonenzyme-derived immunosuppressive IDO1 effects is therefore of high interest. We previously described a novel proteolysis targeting chimera (PROTAC), NU223612, that degrades IDO1 in cultured human glioblastoma (GBM) cells, as well as in well-established brain tumors, in vivo. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC50 of 5 nM in human GBM cells. Mechanistic studies showed that IDO1 degradation occurred through the ubiquitin-proteasome system and was sustained for at least 2 days, supporting NU227326 as a highly potent IDO1 PROTAC suitable for further studies in GBM and other human cancers.
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Affiliation(s)
- Paige
J. Monsen
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
| | - Prashant V. Bommi
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Arabela A. Grigorescu
- Department
of Molecular Biosciences, Northwestern University
Weinberg College of Arts and Sciences, Evanston, Illinois 60208, United States
| | - Kristen L. Lauing
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Yingyu Mao
- High-Throughput
Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States
| | - Payton Berardi
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Lijie Zhai
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Oluwatomilayo Ojo
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Manon Penco-Campillo
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Taylor Koch
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Michael Egozi
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Sonam Jha
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
| | - Sara F. Dunne
- High-Throughput
Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States
| | - Hong Jiang
- HD
Biosciences
(China) Co., Ltd., A WuXi AppTec Company, Shanghai 201201, China
| | - Guiqin Song
- HD
Biosciences
(China) Co., Ltd., A WuXi AppTec Company, Shanghai 201201, China
| | - Fang Zhang
- HD
Biosciences
(China) Co., Ltd., A WuXi AppTec Company, Shanghai 201201, China
| | - Steven Kregel
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
- Cardinal
Bernardin Cancer Center, Maywood, Illinois 60153, United States
| | - Ali Vaziri-Gohar
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
- Cardinal
Bernardin Cancer Center, Maywood, Illinois 60153, United States
- Department
of Surgery, Loyola University Chicago Stritch
School of Medicine, Maywood, Illinois 60153, United States
| | - Sean W. Fanning
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
| | - Pilar Sanchez-Gomez
- Neuro-Oncology
Unit, Unidad Funcional de Investigación
en Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos
III (ISCIII), Madrid 28029, Spain
| | - Jacob M. Allen
- Department
of Health and Kinesiology, University of
Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Bakhtiar Yamini
- Department
of Neurological Surgery, University of Chicago
Medicine, Chicago, Illinois 60637, United States
| | - Rimas V. Lukas
- Department
of Neurology, Northwestern University Feinberg
School of Medicine, Chicago, Illinois 60611, United States
| | - Derek A. Wainwright
- Department
of Cancer Biology, Loyola University Chicago
Stritch School of Medicine, Maywood, Illinois 60153, United States
- Cardinal
Bernardin Cancer Center, Maywood, Illinois 60153, United States
- Department
of Neurological Surgery, Loyola University
Medical Center, Maywood, Illinois 60153, United States
| | - Gary E. Schiltz
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
- Robert
H. Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department
of Pharmacology, Northwestern University,
Feinberg School of Medicine, Chicago, Illinois 60611 United States
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Monsen PJ, Bommi PV, Grigorescu AA, Lauing KL, Mao Y, Berardi P, Zhai L, Ojo O, Penco-Campillo M, Koch T, Egozi M, Jha SV, Dunne SF, Jiang H, Song G, Zhang F, Kregel S, Vaziri-Gohar A, Fanning S, Sanchez-Gomez P, Allen JM, Yamini B, Lukas RV, Wainwright DA, Schiltz GE. Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.07.631731. [PMID: 39829781 PMCID: PMC11741391 DOI: 10.1101/2025.01.07.631731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is a potently immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and non-enzymatic functions. Pharmacological therapies targeting IDO1 enzyme activity have generally failed to improve the overall survival of patients with cancer. Developing new therapeutic agents that are capable of neutralizing both enzyme-and non-enzyme-derived immunosuppressive IDO1 effects is therefore of high interest. We previously described the development of a novel Proteolysis Targeting Chimera (PROTAC), NU223612, that degrades IDO1 in cultured human glioblastoma (GBM) cells, as well as in well-established brain tumors, in vivo . In this study, we rationally optimized the composition, rigidity, and linker orientation of the PROTAC structure to create NU227326, which degrades IDO1 with a DC 50 of 5 nM in human GBM cells. Mechanistic studies showed that IDO1 degradation occurred through the ubiquitin-proteasome system and was sustained for at least 2 days, supporting NU227326 as a highly potent IDO1 PROTAC suitable for further studies in GBM and other human cancers.
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3
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Kurnit KC, Odunsi K. Harnessing Antitumor Immunity in Ovarian Cancer. Cold Spring Harb Perspect Med 2024; 14:a041336. [PMID: 38621830 PMCID: PMC11610759 DOI: 10.1101/cshperspect.a041336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
Despite progress in other tumor types, immunotherapy is not yet part of the standard of care treatment for high-grade serous ovarian cancer patients. Although tumor infiltration by T cells is frequently observed in patients with ovarian cancer, clinical responses to immunotherapy remain low. Mechanisms for immune resistance in ovarian cancer have been explored and may provide insight into future approaches to improve response to immunotherapy agents. In this review, we discuss what is known about the immune landscape in ovarian cancer, review the available data for immunotherapy-based strategies in these patients, and provide possible future directions.
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Affiliation(s)
- Katherine C Kurnit
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois 60637, USA
| | - Kunle Odunsi
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois 60637, USA
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois 60637, USA
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Wang Y, Gao S, Liu Y, Li Y, Yao H, Han Y, Liu X. Association between gut microbiota, plasma metabolites, and ovarian cancer: A Mendelian randomization study. Medicine (Baltimore) 2024; 103:e40479. [PMID: 39533575 PMCID: PMC11556969 DOI: 10.1097/md.0000000000040479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Numerous studies have demonstrated a correlation between alterations in gut microbiota (GM) and levels of body metabolites in ovarian cancer (OC). However, the specific causal relationships underlying these associations remain unclear. This study utilized summary statistics of GM from the MiBioGen consortium, along with an unprecedented dataset comprising 1091 blood metabolites and 309 metabolite ratios from the UK Biobank, in conjunction with OC data from the FinnGen Consortium R9 release. We conducted bidirectional Mendelian randomization (MR) analyses to investigate the causal relationships between GM and OC. Additionally, a two-step MR approach was employed to identify potential mediating metabolites. Our analysis revealed significant associations between 6 specific microbiota taxa and OC. Furthermore, we identified several plasma metabolites that act as mediators of the association between GM and OC. In the two-step MR analysis, we observed a negative correlation between 4-methoxyphenol sulfate and pregnenetriol disulfate levels with OC. The genus Lachnospiraceae UCG008 potentially increases the risk of OC by decreasing 4-methoxyphenol sulfate levels, while the genus Howardella may elevate the risk of OC by reducing pregnenetriol disulfate levels, with mediation proportions of 22.35% and 4.23%, respectively. Additionally, levels of dilinoleoyl-GPE (18:2/18:2) and N-acetylkynurenine (2) were positively correlated with OC. The inhibitory effect of the genus Ruminococcus 1 on OC may be mediated through 1,2-dilinoleoyl-GPE (18:2/18:2) and N-acetylkynurenine (2), with mediation proportions of 10.15% and 11.32%, respectively. Our findings highlight the complex relationship among GM, plasma metabolites, and OC. The identified associations and mediation effects offer valuable insights into potential therapeutic approaches targeting GM for the management of OC.
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Affiliation(s)
- Yu Wang
- The Pathology Department of Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | | | - Yangyu Liu
- The Pathology Department of Shanxi Provincial People’ Hospital, Shanxi Medical University, Taiyuan, China
| | - Yongai Li
- Medical Imaging Center of Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | - Hui Yao
- The Gynecology of Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | - Yan Han
- The Gynecology of Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | - Xinyue Liu
- The Gynecology of Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, China
- The Gynecology Department of Shanxi Provincial People’ Hospital, Shanxi Medical University, Taiyuan, China
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Myong S, Nguyen AQ, Challa S. Biological Functions and Therapeutic Potential of NAD + Metabolism in Gynecological Cancers. Cancers (Basel) 2024; 16:3085. [PMID: 39272943 PMCID: PMC11394644 DOI: 10.3390/cancers16173085] [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: 07/31/2024] [Revised: 08/31/2024] [Accepted: 08/31/2024] [Indexed: 09/15/2024] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an important cofactor for both metabolic and signaling pathways, with the dysregulation of NAD+ levels acting as a driver for diseases such as neurodegeneration, cancers, and metabolic diseases. NAD+ plays an essential role in regulating the growth and progression of cancers by controlling important cellular processes including metabolism, transcription, and translation. NAD+ regulates several metabolic pathways such as glycolysis, the citric acid (TCA) cycle, oxidative phosphorylation, and fatty acid oxidation by acting as a cofactor for redox reactions. Additionally, NAD+ acts as a cofactor for ADP-ribosyl transferases and sirtuins, as well as regulating cellular ADP-ribosylation and deacetylation levels, respectively. The cleavage of NAD+ by CD38-an NAD+ hydrolase expressed on immune cells-produces the immunosuppressive metabolite adenosine. As a result, metabolizing and maintaining NAD+ levels remain crucial for the function of various cells found in the tumor microenvironment, hence its critical role in tissue homeostasis. The NAD+ levels in cells are maintained by a balance between NAD+ biosynthesis and consumption, with synthesis being controlled by the Preiss-Handler, de novo, and NAD+ salvage pathways. The primary source of NAD+ synthesis in a variety of cell types is directed by the expression of the enzymes central to the three biosynthesis pathways. In this review, we describe the role of NAD+ metabolism and its synthesizing and consuming enzymes' control of cancer cell growth and immune responses in gynecologic cancers. Additionally, we review the ongoing efforts to therapeutically target the enzymes critical for NAD+ homeostasis in gynecologic cancers.
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Affiliation(s)
- Subin Myong
- The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA
| | - Anh Quynh Nguyen
- Department of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA
| | - Sridevi Challa
- The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA
- Department of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA
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Grobben Y. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Front Immunol 2024; 15:1440269. [PMID: 39211039 PMCID: PMC11359565 DOI: 10.3389/fimmu.2024.1440269] [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: 05/29/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Despite the immune system's role in the detection and eradication of abnormal cells, cancer cells often evade elimination by exploitation of various immune escape mechanisms. Among these mechanisms is the ability of cancer cells to upregulate amino acid-metabolizing enzymes, or to induce these enzymes in tumor-infiltrating immunosuppressive cells. Amino acids are fundamental cellular nutrients required for a variety of physiological processes, and their inadequacy can severely impact immune cell function. Amino acid-derived metabolites can additionally dampen the anti-tumor immune response by means of their immunosuppressive activities, whilst some can also promote tumor growth directly. Based on their evident role in tumor immune escape, the amino acid-metabolizing enzymes glutaminase 1 (GLS1), arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and interleukin 4 induced 1 (IL4I1) each serve as a promising target for immunotherapeutic intervention. This review summarizes and discusses the involvement of these enzymes in cancer, their effect on the anti-tumor immune response and the recent progress made in the preclinical and clinical evaluation of inhibitors targeting these enzymes.
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Gien LT, Enserro DM, Block MS, Waggoner S, Duska LR, Wahner-Hendrickson AE, Thaker PH, Backes F, Kidd M, Muller CY, DiSilvestro PA, Covens A, Gershenson DM, Moore KN, Aghajanian C, Coleman RL. Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: An NRG oncology study GY016. Gynecol Oncol 2024; 186:61-68. [PMID: 38603953 PMCID: PMC11265792 DOI: 10.1016/j.ygyno.2024.03.027] [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: 12/26/2023] [Revised: 02/28/2024] [Accepted: 03/28/2024] [Indexed: 04/13/2024]
Abstract
INTRODUCTION Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC. METHODS This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). RESULTS Between September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply. CONCLUSIONS Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC.
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MESH Headings
- Humans
- Female
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Middle Aged
- Aged
- Ovarian Neoplasms/drug therapy
- Ovarian Neoplasms/pathology
- Ovarian Neoplasms/mortality
- Adult
- Aged, 80 and over
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/pathology
- Sulfonamides/administration & dosage
- Sulfonamides/adverse effects
- Sulfonamides/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Adenocarcinoma, Clear Cell/drug therapy
- Adenocarcinoma, Clear Cell/pathology
- Adenocarcinoma, Clear Cell/mortality
- Progression-Free Survival
- Oximes
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Affiliation(s)
- Lilian T Gien
- Sunnybrook Odette Cancer Centre, Toronto, ONT M4N 3M5, USA.
| | - Danielle M Enserro
- NRG Statistical Center, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | | | | | - Linda R Duska
- University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
| | | | - Premal H Thaker
- Washington University and Siteman Cancer Center, St. Louis, MO 63110, USA.
| | - Floor Backes
- Ohio State University Comprehensive Cancer Center, Hilliard, OH 43026, USA.
| | - Michael Kidd
- Montana Cancer Society NCORP, Billings Clinic Cancer Center, Billings, MT 59101, USA.
| | - Carolyn Y Muller
- New Mexico Minority Underserved NCORP, UNM Comprehensive Cancer Center, Albuquerque, NM 87131, USA.
| | | | - Allan Covens
- Sunnybrook Odette Cancer Centre, Toronto, ONT M4N 3M5, USA.
| | | | - Kathleen N Moore
- Oklahoma University Health Stephenson Cancer Center, Oklahoma City, OK 73104, USA.
| | - Carol Aghajanian
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - Robert L Coleman
- US Oncology Network, 9180 Pinecroft Ave., Shenandoah, TX 77030, USA.
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Bali P, Lozano-Pope I, Hernandez J, Estrada MV, Corr M, Turner MA, Bouvet M, Benner C, Obonyo M. TRIF-IFN-I pathway in Helicobacter-induced gastric cancer in an accelerated murine disease model and patient biopsies. iScience 2024; 27:109457. [PMID: 38558931 PMCID: PMC10981133 DOI: 10.1016/j.isci.2024.109457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 12/20/2023] [Accepted: 03/07/2024] [Indexed: 04/04/2024] Open
Abstract
Helicobacter pylori (H. pylori) infection is a known cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the underlying mechanisms by which H. pylori infection triggers these disorders are still not clearly understood. Gastric cancer is a slow progressing disease, which makes it difficult to study. We have developed an accelerated disease progression mouse model, which leverages mice deficient in the myeloid differentiation primary response 88 gene (Myd88-/-) infected with Helicobacter felis (H. felis). Using this model and gastric biopsy samples from patients, we report that activation of the Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-β (TRIF)-type I interferon (IFN-I) signaling pathway promotes Helicobacter-induced disease progression toward severe gastric pathology and gastric cancer development. Further, results implicated downstream targets of this pathway in disease pathogenesis. These findings may facilitate stratification of Helicobacter-infected patients and thus enable treatment prioritization of patients.
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Affiliation(s)
- Prerna Bali
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Ivonne Lozano-Pope
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Jonathan Hernandez
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Monica V. Estrada
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Maripat Corr
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Michael A. Turner
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Michael Bouvet
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Christopher Benner
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Marygorret Obonyo
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
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9
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Engin AB, Engin A. Tryptophan Metabolism in Obesity: The Indoleamine 2,3-Dioxygenase-1 Activity and Therapeutic Options. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:629-655. [PMID: 39287867 DOI: 10.1007/978-3-031-63657-8_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Obesity activates both innate and adaptive immune responses in adipose tissue. Adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-γ)-producing cluster of differentiation (CD)4+ T cells in adipose tissue of obese subjects. The increased formation of neopterin and degradation of tryptophan may result in decreased T-cell responsiveness and lead to immunodeficiency. The activity of inducible indoleamine 2,3-dioxygenase-1 (IDO1) plays a major role in pro-inflammatory, IFN-γ-dominated settings. The expression of several kynurenine pathway enzyme genes is significantly increased in obesity. IDO1 in obesity shifts tryptophan metabolism from serotonin and melatonin synthesis to the formation of kynurenines and increases the ratio of kynurenine to tryptophan as well as with neopterin production. Reduction in serotonin (5-hydroxytryptamine; 5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. According to the monoamine-deficiency hypothesis, a deficiency of cerebral serotonin is involved in neuropsychiatric symptomatology of depression, mania, and psychosis. Indeed, bipolar disorder (BD) and related cognitive deficits are accompanied by a higher prevalence of overweight and obesity. Furthermore, the accumulation of amyloid-β in Alzheimer's disease brains has several toxic effects as well as IDO induction. Hence, abdominal obesity is associated with vascular endothelial dysfunction. kynurenines and their ratios are prognostic parameters in coronary artery disease. Increased kynurenine/tryptophan ratio correlates with increased intima-media thickness and represents advanced atherosclerosis. However, after bariatric surgery, weight reduction does not lead to the normalization of IDO1 activity and atherosclerosis. IDO1 is involved in the mechanisms of immune tolerance and in the concept of tumor immuno-editing process in cancer development. Serum IDO1 activity is still used as a parameter in cancer development and growth. IDO-producing tumors show a high total IDO immunostaining score, and thus, using IDO inhibitors, such as Epacadostat, Navoximod, and L isomer of 1-methyl-tryptophan, seems an important modality for cancer treatment. There is an inverse correlation between serum folate concentration and body mass index, thus folate deficiency leads to hyperhomocysteinemia-induced oxidative stress. Immune checkpoint blockade targeting cytotoxic T-lymphocyte-associated protein-4 synergizes with imatinib, which is an inhibitor of mitochondrial folate-mediated one-carbon (1C) metabolism. Antitumor effects of imatinib are enhanced by increasing T-cell effector function in the presence of IDO inhibition. Combining IDO targeting with chemotherapy, radiotherapy and/or immunotherapy, may be an effective tool against a wide range of malignancies. However, there are some controversial results regarding the efficacy of IDO1 inhibitors in cancer treatment.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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10
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Luo Z, Eichinger KM, Zhang A, Li S. Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy. Cancer Lett 2023; 575:216396. [PMID: 37739209 PMCID: PMC10591810 DOI: 10.1016/j.canlet.2023.216396] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/28/2023] [Accepted: 09/12/2023] [Indexed: 09/24/2023]
Abstract
Recent discoveries in cancer metabolism have revealed promising metabolic targets to modulate cancer progression, drug response, and anti-cancer immunity. Combination therapy, consisting of metabolic inhibitors and chemotherapeutic or immunotherapeutic agents, offers new opportunities for improved cancer therapy. However, it also presents challenges due to the complexity of cancer metabolic pathways and the metabolic interactions between tumor cells and immune cells. Many studies have been published demonstrating potential synergy between novel inhibitors of metabolism and chemo/immunotherapy, yet our understanding of the underlying mechanisms remains limited. Here, we review the current strategies of altering the metabolic pathways of cancer to improve the anti-cancer effects of chemo/immunotherapy. We also note the need to differentiate the effect of metabolic inhibition on cancer cells and immune cells and highlight nanotechnology as an emerging solution. Improving our understanding of the complexity of the metabolic pathways in different cell populations and the anti-cancer effects of chemo/immunotherapy will aid in the discovery of novel strategies that effectively restrict cancer growth and augment the anti-cancer effects of chemo/immunotherapy.
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Affiliation(s)
- Zhangyi Luo
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Anju Zhang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
| | - Song Li
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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11
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Hoffmann I, Dragomir MP, Monjé N, Keunecke C, Kunze CA, Schallenberg S, Marchenko S, Schmitt WD, Kulbe H, Sehouli J, Braicu IE, Jank P, Denkert C, Darb-Esfahani S, Horst D, Sinn BV, Sers C, Bischoff P, Taube ET. Increased expression of IDO1 is associated with improved survival and increased number of TILs in patients with high-grade serous ovarian cancer. Neoplasia 2023; 44:100934. [PMID: 37703626 PMCID: PMC10502412 DOI: 10.1016/j.neo.2023.100934] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/31/2023] [Indexed: 09/15/2023]
Abstract
BACKGROUND The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays a crucial role in regulating the immune system's response to tumors, but its exact role in cancer, especially in high-grade serous ovarian cancer (HGSOC), remains controversial. We aimed to investigate the prognostic impact of IDO1 expression and its correlation with tumor-infiltrating lymphocytes (TILs) in HGSOC. METHODS Immunohistochemical (IHC) staining and bioimage analysis using the QuPath software were employed to assess IDO1 protein expression in a well-characterized cohort of 507 patients with primary HGSOC. Statistical evaluation was performed using SPSS, and in silico validation considering IDO1 mRNA expression in bulk and single-cell gene expression datasets was conducted. Additionally, IDO1 expression in interferon-gamma (IFNG) stimulated HGSOC cell lines was analyzed. RESULTS Our findings revealed that IDO1 protein and mRNA expression serve as positive prognostic markers for overall survival (OS) and progression-free survival (PFS) in HGSOC. High IDO1 expression was associated with a significant improvement in OS by 21 months (p < 0.001) and PFS by 6 months (p = 0.016). Notably, elevated IDO1 expression correlated with an increased number of CD3+ (p < 0.001), CD4+ (p < 0.001), and CD8+ TILs (p < 0.001). Furthermore, high IDO1 mRNA expression and protein level were found to be associated with enhanced responsiveness to pro-inflammatory cytokines, particularly IFNG. CONCLUSIONS Our study provides evidence that IDO1 expression serves as a positive prognostic marker in HGSOC and is associated with an increased number of CD3+, CD4+ and CD8+ TILs. Understanding the intricate relationship between IDO1, TILs, and the tumor microenvironment may hold the key to improving outcomes in HGSOC.
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Affiliation(s)
- Inga Hoffmann
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Mihnea P Dragomir
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Nanna Monjé
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Carlotta Keunecke
- Department of Gynecology, European Competence Center for Ovarian Cancer, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Catarina Alisa Kunze
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Simon Schallenberg
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Sofya Marchenko
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Wolfgang D Schmitt
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Hagen Kulbe
- Department of Gynecology, European Competence Center for Ovarian Cancer, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Tumorbank Ovarian Cancer Network, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Jalid Sehouli
- Department of Gynecology, European Competence Center for Ovarian Cancer, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Tumorbank Ovarian Cancer Network, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Ioana Elena Braicu
- Department of Gynecology, European Competence Center for Ovarian Cancer, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Tumorbank Ovarian Cancer Network, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Paul Jank
- Institute of Pathology, Philipps-University Marburg and University Hospital Marburg, Baldingerstraße, 35043 Marburg, Germany
| | - Carsten Denkert
- Institute of Pathology, Philipps-University Marburg and University Hospital Marburg, Baldingerstraße, 35043 Marburg, Germany
| | - Silvia Darb-Esfahani
- MVZ Pathologie Spandau, Stadtrandstr. 555, 13589 Berlin Spandau; MVZ Pathologie Berlin-Buch, Lindenberger Weg 27, Haus 207, 13125 Berlin
| | - David Horst
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Bruno V Sinn
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Christine Sers
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Philip Bischoff
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Eliane T Taube
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany.
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12
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Bali P, Lozano-Pope I, Hernandez J, Estrada MV, Corr M, Turner MA, Bouvet M, Benner C, Obonyo M. Activation of the TRIF pathway and downstream targets results in the development of precancerous lesions during infection with Helicobacter. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.04.543598. [PMID: 37333238 PMCID: PMC10274671 DOI: 10.1101/2023.06.04.543598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Helicobacter pylori ( H. pylori) infection is an established cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the mechanism by which infection with H. pylori causes these disorders is still not clearly understood. This is due to insufficient knowledge of pathways that promote H. pylori -induced disease progression. We have established a Helicobacter -induced accelerated disease progression mouse model, which involves infecting mice deficient in the myeloid differentiation primary response 88 gene ( Myd88 -/- ) with H. felis . Using this model, we report here that that progression of H. felis -induced inflammation to high-grade dysplasia was associated with activation of type I interferon (IFN-I) signaling pathway and upregulation of related downstream target genes, IFN-stimulated genes (ISGs). These observations were further corroborated by the enrichment of ISRE motifs in the promoters of upregulated genes. Further we showed that H. felis -induced inflammation in mice deficient in Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-β (TRIF, Trif Lps 2 ) did not progress to severe gastric pathology, indicating a role of the TRIF signaling pathway in disease pathogenesis and progression. Indeed, survival analysis in gastric biopsy samples from gastric cancer patients illustrated that high expression of Trif was significantly associated with poor survival in gastric cancer.
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13
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Xue C, Li G, Zheng Q, Gu X, Shi Q, Su Y, Chu Q, Yuan X, Bao Z, Lu J, Li L. Tryptophan metabolism in health and disease. Cell Metab 2023; 35:1304-1326. [PMID: 37352864 DOI: 10.1016/j.cmet.2023.06.004] [Citation(s) in RCA: 293] [Impact Index Per Article: 146.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/10/2023] [Accepted: 06/05/2023] [Indexed: 06/25/2023]
Abstract
Tryptophan (Trp) metabolism primarily involves the kynurenine, 5-hydroxytryptamine, and indole pathways. A variety of bioactive compounds produced via Trp metabolism can regulate various physiological functions, including inflammation, metabolism, immune responses, and neurological function. Emerging evidence supports an intimate relationship between Trp metabolism disorder and diseases. The levels or ratios of Trp metabolites are significantly associated with many clinical features. Additionally, studies have shown that disease progression can be controlled by modulating Trp metabolism. Indoleamine-2,3-dioxygenase, Trp-2,3-dioxygenase, kynurenine-3-monooxygenase, and Trp hydroxylase are the rate-limiting enzymes that are critical for Trp metabolism. These key regulatory enzymes can be targeted for treating several diseases, including tumors. These findings provide novel insights into the treatment of diseases. In this review, we have summarized the recent research progress on the role of Trp metabolites in health and disease along with their clinical applications.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ganglei Li
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qiuxian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yuanshuai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhengyi Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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14
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Borella F, Fucina S, Mangherini L, Cosma S, Carosso AR, Cusato J, Cassoni P, Bertero L, Katsaros D, Benedetto C. Hormone Receptors and Epithelial Ovarian Cancer: Recent Advances in Biology and Treatment Options. Biomedicines 2023; 11:2157. [PMID: 37626654 PMCID: PMC10452581 DOI: 10.3390/biomedicines11082157] [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: 04/27/2023] [Revised: 06/03/2023] [Accepted: 07/22/2023] [Indexed: 08/27/2023] Open
Abstract
Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women. Despite advances in diagnosis and treatment, EOC remains a challenging disease to manage, and the 5-year survival rate is still poor. The role of hormone receptors (HRs) in EOC carcinogenesis and prognosis has been actively explored; however, the role of hormone therapy (HT) in the treatment of these tumors is not well established. Most available data on HT mainly come from retrospective series and small early clinical trials. Several of these studies suggest that HT may have a role in adjuvant, maintenance therapy, or in the case of recurrent disease, especially for some subtypes of EOC (e.g., low-grade serous EOC). Furthermore, HT has recently been combined with targeted therapies, but most studies evaluating these combinations are still ongoing. The main aim of this review is to provide an overview of the progress made in the last decade to characterize the biological and prognostic role of HRs for EOC and the developments in their therapeutic targeting through HT.
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Affiliation(s)
- Fulvio Borella
- Gynecology and Obstetrics 1U, Departments of Surgical Sciences, City of Health and Science, University of Turin, 10126 Turin, Italy; (S.F.); (S.C.); (A.R.C.); (D.K.); (C.B.)
| | - Stefano Fucina
- Gynecology and Obstetrics 1U, Departments of Surgical Sciences, City of Health and Science, University of Turin, 10126 Turin, Italy; (S.F.); (S.C.); (A.R.C.); (D.K.); (C.B.)
| | - Luca Mangherini
- Pathology Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (L.M.); (P.C.); (L.B.)
| | - Stefano Cosma
- Gynecology and Obstetrics 1U, Departments of Surgical Sciences, City of Health and Science, University of Turin, 10126 Turin, Italy; (S.F.); (S.C.); (A.R.C.); (D.K.); (C.B.)
| | - Andrea Roberto Carosso
- Gynecology and Obstetrics 1U, Departments of Surgical Sciences, City of Health and Science, University of Turin, 10126 Turin, Italy; (S.F.); (S.C.); (A.R.C.); (D.K.); (C.B.)
| | - Jessica Cusato
- Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy;
| | - Paola Cassoni
- Pathology Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (L.M.); (P.C.); (L.B.)
| | - Luca Bertero
- Pathology Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (L.M.); (P.C.); (L.B.)
| | - Dionyssios Katsaros
- Gynecology and Obstetrics 1U, Departments of Surgical Sciences, City of Health and Science, University of Turin, 10126 Turin, Italy; (S.F.); (S.C.); (A.R.C.); (D.K.); (C.B.)
| | - Chiara Benedetto
- Gynecology and Obstetrics 1U, Departments of Surgical Sciences, City of Health and Science, University of Turin, 10126 Turin, Italy; (S.F.); (S.C.); (A.R.C.); (D.K.); (C.B.)
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15
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Struckmeier AK, Radermacher A, Fehrenz M, Bellin T, Alansary D, Wartenberg P, Boehm U, Wagner M, Scheller A, Hess J, Moratin J, Freudlsperger C, Hoffmann J, Thurner L, Roemer K, Freier K, Horn D. IDO1 is highly expressed in macrophages of patients in advanced tumour stages of oral squamous cell carcinoma. J Cancer Res Clin Oncol 2023; 149:3623-3635. [PMID: 35963900 PMCID: PMC10314853 DOI: 10.1007/s00432-022-04277-7] [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: 08/02/2022] [Accepted: 08/09/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE Strategies for Indolamine-2,3-dioxygenase 1 (IDO1) inhibition in cancer immunotherapy once produced encouraging results, but failed in clinical trials. Recent evidence indicates that immune cells in the tumour microenvironment, especially macrophages, contribute to immune dysregulation and therefore might play a critical role in drug resistance. METHODS In this study, we investigated the significance of IDO1 expressing immune cells in primary tumours and corresponding lymph node metastases (LNMs) in oral squamous cell carcinoma (OSCC) by immunohistochemistry. The link between IDO1 and macrophages was investigated by flow cytometry in tumour tissue, healthy adjacent tissue and peripheral blood mononuclear cells (PBMCs). IDO1 activity (measured as Kynurenine/Tryptophan ratio) was assessed by ELISAs. RESULTS High IDO1 expression in tumour-infiltrating immune cells was significantly correlated with advanced stages [Spearman's rank correlation (SRC), p = 0.027] and reduced progression-free survival (multivariate Cox regression, p = 0.034). IDO1 was significantly higher expressed in PBMCs of patients in advanced stages than in healthy controls (ANOVA, p < 0.05) and IDO1+ macrophages were more abundant in intratumoural areas than peritumoural (t test, p < 0.001). IDO1 expression in PBMCs was significantly correlated with IDO1 activity in serum (SRC, p < 0.05). IDO1 activity was significantly higher in patients with LNMs (t test, p < 0.01). CONCLUSION All in all, IDO1 expressing immune cells, especially macrophages, are more abundant in advanced stages of OSCC and are associated with reduced progression-free survival. Further investigations are needed to explore their role in local and systemic immune response. The IDO1 activity might be a suitable biomarker of metastasis in OSCC patients.
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Affiliation(s)
- Ann-Kristin Struckmeier
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany.
| | - Anne Radermacher
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
| | - Michael Fehrenz
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
| | - Tamara Bellin
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
| | - Dalia Alansary
- Institute of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Saar, Germany
| | - Philipp Wartenberg
- Department of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Saar, Germany
| | - Ulrich Boehm
- Department of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Saar, Germany
| | - Mathias Wagner
- Department of Pathology, Saarland University Medical Center, Homburg, Saar, Germany
| | - Anja Scheller
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Saar, Germany
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Julius Moratin
- Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Freudlsperger
- Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Jürgen Hoffmann
- Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Lorenz Thurner
- Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology, and Rheumatology), Saarland University Medical Center, Homburg, Saar, Germany
| | - Klaus Roemer
- José Carreras Center for Immuno and Gene Therapy, Saarland University, Homburg, Saar, Germany
| | - Kolja Freier
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
| | - Dominik Horn
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
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Yoon WH, DeFazio A, Kasherman L. Immune checkpoint inhibitors in ovarian cancer: where do we go from here? CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:358-377. [PMID: 37457131 PMCID: PMC10344730 DOI: 10.20517/cdr.2023.13] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 05/22/2023] [Accepted: 05/31/2023] [Indexed: 07/18/2023]
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and despite advancements in therapeutics, most women unfortunately still succumb to their disease. Immunotherapies, in particular immune checkpoint inhibitors (ICI), have been therapeutically transformative in many tumour types, including gynaecological malignancies such as cervical and endometrial cancer. Unfortunately, these therapeutic successes have not been mirrored in ovarian cancer clinical studies. This review provides an overview of the ovarian tumour microenvironment (TME), particularly factors associated with survival, and explores current research into immunotherapeutic strategies in EOC, with an exploratory focus on novel therapeutics in navigating drug resistance.
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Affiliation(s)
- Won-Hee Yoon
- Department of Medical Oncology, Blacktown Cancer and Haematology Centre, Blacktown Hospital, Blacktown 2148, Australia
- Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead 2145, Australia
- Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia
| | - Anna DeFazio
- Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia
- Department of Gynecological Oncology, Westmead Hospital, Westmead 2145, Australia
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council New South Wales, Sydney 2011, Australia
| | - Lawrence Kasherman
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia
- Department of Medical Oncology, Illawarra Cancer Care Centre, Wollongong 2500, Australia
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Wang M, Zhang J, Wu Y. Tumor metabolism rewiring in epithelial ovarian cancer. J Ovarian Res 2023; 16:108. [PMID: 37277821 DOI: 10.1186/s13048-023-01196-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 05/29/2023] [Indexed: 06/07/2023] Open
Abstract
The mortality rate of epithelial ovarian cancer (EOC) remains the first in malignant tumors of the female reproductive system. The characteristics of rapid proliferation, extensive implanted metastasis, and treatment resistance of cancer cells require an extensive metabolism rewiring during the progression of cancer development. EOC cells satisfy their rapid proliferation through the rewiring of perception, uptake, utilization, and regulation of glucose, lipids, and amino acids. Further, complete implanted metastasis by acquiring a superior advantage in microenvironment nutrients competing. Lastly, success evolves under the treatment stress of chemotherapy and targets therapy. Understanding the above metabolic characteristics of EOCs helps to find new methods of its treatment.
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Affiliation(s)
- Ming Wang
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, 17 Qihelou St, Dongcheng District, Beijing, 100006, China
| | - Jingjing Zhang
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, 17 Qihelou St, Dongcheng District, Beijing, 100006, China
| | - Yumei Wu
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, 17 Qihelou St, Dongcheng District, Beijing, 100006, China.
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18
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Jian D, Lianghao Z, Yunge G, Ligang C, Biliang C, Xiaohui L. A Prognostic Model Based on Metabolism-Related Genes for Patients with Ovarian Cancer. DOKL BIOCHEM BIOPHYS 2023; 510:110-122. [PMID: 37582873 DOI: 10.1134/s1607672923600082] [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: 01/20/2023] [Revised: 03/03/2023] [Accepted: 03/09/2023] [Indexed: 08/17/2023]
Abstract
Metabolism-associated genes (MAGs) are important regulators of tumor progression and can affect a variety of physiological processes. In this study, we focused on the relationship between MAGs and Ovarian cancer (OC) prognosis. METHOD Metabolism-related genes were extracted from the Cancer Genome Atlas (TCGA) database. Through univariate COX and lasso regression models, a dynamic risk model based on MAGs was established. Compared with other clinical factors, demonstrated the ability of the model to predict the prognosis of patients with OC. The clinical samples were used to verify the expression of these MAGs. RESULTS A metabolism-associated gene signature was constructed by LASSO Cox regression analysis in OC, which was composed of 3-MAGs (PTGIS, AOC3, and IDO1). The signature was used to classify the OC patients into high-risk and low-risk groups. The overall survival of the low-risk group was significantly better than that of the high-risk group. The analysis of the therapeutic effect of bevacizumab showed that bevacizumab was not conducive to improving the prognosis of the low-risk group. CONCLUSIONS We constructed a prognostic model of MAGs in OC, which can be used to predict the prognosis of OC patients and may have a good guiding significance in the individualized treatment of patients.
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Affiliation(s)
- Dong Jian
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Zhai Lianghao
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Gao Yunge
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Chen Ligang
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Chen Biliang
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Lv Xiaohui
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China.
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19
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Chen C, Liu X, Chang CY, Wang HY, Wang RF. The Interplay between T Cells and Cancer: The Basis of Immunotherapy. Genes (Basel) 2023; 14:genes14051008. [PMID: 37239368 DOI: 10.3390/genes14051008] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/17/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body's defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments.
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Affiliation(s)
- Christina Chen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Xin Liu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Che-Yu Chang
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Helen Y Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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20
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Lai W, Liao J, Li X, Liang P, He L, Huang K, Liang X, Wang Y. Characterization of the microenvironment in different immune-metabolism subtypes of cervical cancer with prognostic significance. Front Genet 2023; 14:1067666. [PMID: 36816023 PMCID: PMC9935837 DOI: 10.3389/fgene.2023.1067666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 01/20/2023] [Indexed: 02/05/2023] Open
Abstract
Introduction: Immune cell infiltration and metabolic reprogramming may have great impact on the tumorigenesis and progression of malignancies. The interaction between these two factors in cervical cancer remains to be clarified. Here we constructed a gene set containing immune and metabolism related genes and we applied this gene set to molecular subtyping of cervical cancer. Methods: Bulk sequencing and single-cell sequencing data were downloaded from the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database respectively. Immune and metabolism related genes were collected from Immport and Kyoto encyclopedia of genes and genomes (KEGG) database respectively. Unsupervised consensus clustering was performed to identify the molecular subtypes. Cibersort was applied to evaluate the immune cells infiltration status. Differential expression analysis and Gene set enrichment analysis (GSEA) were performed to characterize the molecular pattern of different subtypes. Multivariate Cox regression analysis was used for prognosis prediction model construction and receiver operating characteristic (ROC) curve was used for performance evaluation. The hub genes in the model were verified in single-cell sequencing dataset and clinical specimens. In vitro experiments were performed to validate the findings in our research. Results: Three subtypes were identified with prognostic implications. C1 subgroup was in an immunosuppressive state with activation of mitochondrial cytochrome P450 metabolism, C2 had poor immune cells infiltration and was characterized by tRNA anabolism, and the C3 subgroup was in an inflammatory state with activation of aromatic amino acid synthesis. The area under the ROC curve of the constructed model was 0.8, which showed better performance than clinical features. IMPDH1 was found to be significantly upregulated in tumor tissue and it was demonstrated that IMPDH1 could be a novel therapeutic target in vitro. Discussion: In summary, our findings suggested novel molecular subtypes of cervical cancer with distinct immunometabolic profiles and uncovered a novel therapeutic target.
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Affiliation(s)
- Wujiang Lai
- Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jinrong Liao
- Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoxuan Li
- Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Peili Liang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,Center for Reproductive Medicine/Department of Fetal Medicine and Prenatal Diagnosis/BioResource Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Liqing He
- Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Keke Huang
- Department of Obstetrics, Shunde Hospital, The First People’s Hospital of Shunde, Southern Medical University, Foshan, Guangdong, China,*Correspondence: Keke Huang, ; Xiaomei Liang, ; Yifeng Wang,
| | - Xiaomei Liang
- Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China,*Correspondence: Keke Huang, ; Xiaomei Liang, ; Yifeng Wang,
| | - Yifeng Wang
- Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China,*Correspondence: Keke Huang, ; Xiaomei Liang, ; Yifeng Wang,
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21
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Grobben Y, den Ouden JE, Aguado C, van Altena AM, Kraneveld AD, Zaman GJR. Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1. Cancers (Basel) 2023; 15:cancers15030893. [PMID: 36765849 PMCID: PMC9913486 DOI: 10.3390/cancers15030893] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/19/2023] [Accepted: 01/28/2023] [Indexed: 02/04/2023] Open
Abstract
The molecular mechanisms contributing to immune suppression in ovarian cancer are not well understood, hampering the successful application of immunotherapy. Amino acid-metabolizing enzymes are known to contribute to the immune-hostile environment of various tumors through depletion of amino acids and production of immunosuppressive metabolites. We aimed to collectively evaluate the activity of these enzymes in high-grade serous ovarian cancer patients by performing targeted metabolomics on plasma and ascites samples. Whereas no indication was found for enhanced l-arginine or l-glutamine metabolism by immunosuppressive enzymes in ovarian cancer patients, metabolism of l-tryptophan by indoleamine 2,3-dioxygenase 1 (IDO1) was significantly elevated compared to healthy controls. Moreover, high levels of l-phenylalanine- and l-tyrosine-derived metabolites associated with interleukin 4 induced 1 (IL4I1) activity were found in ovarian cancer ascites samples. While l-tryptophan is a major substrate of both IDO1 and IL4I1, only its enhanced conversion into l-kynurenine by IDO1 could be detected, despite the observed activity of IL4I1 on its other substrates. In ascites of ovarian cancer patients, metabolite levels were higher compared to those in plasma, demonstrating the value of utilizing this fluid for biomarker identification. Finally, elevated metabolism of l-phenylalanine and l-tyrosine by IL4I1 correlated with disease stage, pointing towards a potential role for IL4I1 in ovarian cancer progression.
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Affiliation(s)
| | - Judith E. den Ouden
- Radboud Institute for Health Sciences, Radboud University Medical Center, Obstetrics and Gynecology, 6525 GA Nijmegen, The Netherlands
| | - Cristina Aguado
- Laboratory of Oncology, Pangaea Oncology, Dexeus University Hospital, 08028 Barcelona, Spain
| | - Anne M. van Altena
- Radboud Institute for Health Sciences, Radboud University Medical Center, Obstetrics and Gynecology, 6525 GA Nijmegen, The Netherlands
| | - Aletta D. Kraneveld
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Guido J. R. Zaman
- Oncolines B.V., 5349 AB Oss, The Netherlands
- Correspondence: ; Tel.: +31-412-700501
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22
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Schossig P, Coskun E, Arsenic R, Horst D, Sehouli J, Bergmann E, Andresen N, Sigler C, Busse A, Keller U, Ochsenreither S. Target Selection for T-Cell Therapy in Epithelial Ovarian Cancer: Systematic Prioritization of Self-Antigens. Int J Mol Sci 2023; 24:ijms24032292. [PMID: 36768616 PMCID: PMC9916968 DOI: 10.3390/ijms24032292] [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: 12/23/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Adoptive T cell-receptor therapy (ACT) could represent a promising approach in the targeted treatment of epithelial ovarian cancer (EOC). However, the identification of suitable tumor-associated antigens (TAAs) as targets is challenging. We identified and prioritized TAAs for ACT and other immunotherapeutic interventions in EOC. A comprehensive list of pre-described TAAs was created and candidates were prioritized, using predefined weighted criteria. Highly ranked TAAs were immunohistochemically stained in a tissue microarray of 58 EOC samples to identify associations of TAA expression with grade, stage, response to platinum, and prognosis. Preselection based on expression data resulted in 38 TAAs, which were prioritized. Along with already published Cyclin A1, the TAAs KIF20A, CT45, and LY6K emerged as most promising targets, with high expression in EOC samples and several identified peptides in ligandome analysis. Expression of these TAAs showed prognostic relevance independent of molecular subtypes. By using a systematic vetting algorithm, we identified KIF20A, CT45, and LY6K to be promising candidates for immunotherapy in EOC. Results are supported by IHC and HLA-ligandome data. The described method might be helpful for the prioritization of TAAs in other tumor entities.
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Affiliation(s)
- Paul Schossig
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Ebru Coskun
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ruza Arsenic
- Department of Pathology, Universitätsklinikum Heidelberg, Heidelberg University, 69120 Heidelberg, Germany
| | - David Horst
- Insitute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Jalid Sehouli
- Department of Gynecology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- Tumorbank Ovarian Cancer Network, 13353 Berlin, Germany
| | - Eva Bergmann
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Nadine Andresen
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Christian Sigler
- Charité Comprehensive Cancer Center, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Antonia Busse
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Ulrich Keller
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Sebastian Ochsenreither
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Charité Comprehensive Cancer Center, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- Correspondence:
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23
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Latosińska JN, Latosińska M, Orzeszko A, Maurin JK. Synthesis and Crystal Structure of Adamantylated 4,5,6,7-Tetrahalogeno-1 H-benzimidazoles Novel Multi-Target Ligands (Potential CK2, M2 and SARS-CoV-2 Inhibitors); X-ray/DFT/QTAIM/Hirshfeld Surfaces/Molecular Docking Study. Molecules 2022; 28:147. [PMID: 36615341 PMCID: PMC9822452 DOI: 10.3390/molecules28010147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
A series of new congeners, 1-[2-(1-adamantyl)ethyl]-1H-benzimidazole (AB) and 1-[2-(1-adamantyl)ethyl]-4,5,6,7-tetrahalogeno-1H-benzimidazole (Hal=Cl, Br, I; tClAB, tBrAB, tIAB), have been synthesized and studied. These novel multi-target ligands combine a benzimidazole ring known to show antitumor activity and an adamantyl moiety showing anti-influenza activity. Their crystal structures were determined by X-ray, while intermolecular interactions were studied using topological Bader's Quantum Theory of Atoms in Molecules, Hirshfeld Surfaces, CLP and PIXEL approaches. The newly synthesized compounds crystallize within two different space groups, P-1 (AB and tIAB) and P21/c (tClAB and tBrAB). A number of intramolecular hydrogen bonds, C-H⋯Hal (Hal=Cl, Br, I), were found in all halogen-containing congeners studied, but the intermolecular C-H⋯N hydrogen bond was detected only in AB and tIAB, while C-Hal⋯π only in tClAB and tBrAB. The interplay between C-H⋯N and C-H⋯Hal hydrogen bonds and a shift from the strong (C-H⋯Cl) to the very weak (C-H⋯I) attractive interactions upon Hal exchange, supplemented with Hal⋯Hal overlapping, determines the differences in the symmetry of crystalline packing and is crucial from the biological point of view. The hypothesis about the potential dual inhibitor role of the newly synthesized congeners was verified using molecular docking and the congeners were found to be pharmaceutically attractive as Human Casein Kinase 2, CK2, inhibitors, Membrane Matrix 2 Protein, M2, blockers and Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2, inhibitors. The addition of adamantyl moiety seems to broaden and modify the therapeutic indices of the 4,5,6,7-tetrahalogeno-1H-benzimidazoles.
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Affiliation(s)
| | - Magdalena Latosińska
- Faculty of Physics, Adam Mickiewicz University, Uniwersytetu Poznańskiego 2, 61-614 Poznań, Poland
| | - Andrzej Orzeszko
- Institute of Chemistry, Warsaw University of Life Sciences, 159C Nowoursynowska St., 02-787 Warsaw, Poland
| | - Jan Krzysztof Maurin
- National Medicines Institute, Chełmska 30/34, 00-750 Warsaw, Poland
- National Centre for Nuclear Research, Andrzeja Sołtana 7, 05-400 Otwock-Świerk, Poland
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24
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Bollu L, Bommi PV, Monsen PJ, Zhai L, Lauing KL, Bell A, Kim M, Ladomersky E, Yang X, Platanias LC, Matei DE, Bonini MG, Munshi HG, Hashizume R, Wu JD, Zhang B, James CD, Chen P, Kocherginsky M, Horbinski C, Cameron MD, Grigorescu AA, Yamini B, Lukas RV, Schiltz GE, Wainwright DA. Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma. J Med Chem 2022; 65:15642-15662. [PMID: 36410047 PMCID: PMC9743093 DOI: 10.1021/acs.jmedchem.2c00771] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Indexed: 11/22/2022]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.
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Affiliation(s)
- Lakshmi
R. Bollu
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Prashant V. Bommi
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Paige J. Monsen
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
| | - Lijie Zhai
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Kristen L. Lauing
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - April Bell
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Miri Kim
- Department
of Neurological Surgery, Loyola University
Medical Center, Maywood, Illinois 60153, United
States
| | - Erik Ladomersky
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Xinyu Yang
- WuXi
AppTec, Shanghai 200131, People’s Republic of China
| | - Leonidas C. Platanias
- Department
of Medicine—Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
| | - Daniela E. Matei
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department
of Obstetrics and Gynecology, Northwestern
University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Marcelo G. Bonini
- Department
of Medicine—Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
| | - Hidayatullah G. Munshi
- Department
of Medicine—Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
| | - Rintaro Hashizume
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department
of Pediatrics − Division of Hematology, Oncology, and Stem
Cell Transplantation, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Jennifer D. Wu
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department
of Urology, Northwestern University Feinberg
School of Medicine, Chicago, Illinois 60611, United States
- Department
of Microbiology-Immunology, Northwestern
University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Bin Zhang
- Department
of Medicine—Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
- Department
of Microbiology-Immunology, Northwestern
University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Charles David James
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Peiwen Chen
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Masha Kocherginsky
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department
of Obstetrics and Gynecology, Northwestern
University Feinberg School of Medicine, Chicago, Illinois 60611, United States
- Department of Preventive Medicine, Northwestern
University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Craig Horbinski
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department of Pathology, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Michael D. Cameron
- Department of Molecular Therapeutics, The
Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
| | - Arabela A. Grigorescu
- Department of Molecular Biosciences, Northwestern
University Weinberg College of Arts and Sciences, Evanston, Illinois 60208, United States
| | - Bakhtiar Yamini
- Department of Neurological Surgery, Division of the Biological Sciences, The University of Chicago, Chicago, Illinois 60637, United States
| | - Rimas V. Lukas
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department
of Neurology, Northwestern University Feinberg
School of Medicine, Chicago, Illinois 60611, United States
| | - Gary E. Schiltz
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department of Pharmacology, Northwestern
University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Derek A. Wainwright
- Department
of Neurological Surgery, Northwestern University
Feinberg School of Medicine, Chicago, Illinois 60611, United States
- Department
of Medicine—Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
- Robert
H.
Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States
- Department
of Microbiology-Immunology, Northwestern
University Feinberg School of Medicine, Chicago, Illinois 60611, United States
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25
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Xu T, Liu Z, Huang L, Jing J, Liu X. Modulating the tumor immune microenvironment with nanoparticles: A sword for improving the efficiency of ovarian cancer immunotherapy. Front Immunol 2022; 13:1057850. [PMID: 36532066 PMCID: PMC9751906 DOI: 10.3389/fimmu.2022.1057850] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 11/21/2022] [Indexed: 12/04/2022] Open
Abstract
With encouraging antitumor effects, immunotherapy represented by immune checkpoint blockade has developed into a mainstream cancer therapeutic modality. However, only a minority of ovarian cancer (OC) patients could benefit from immunotherapy. The main reason is that most OC harbor a suppressive tumor immune microenvironment (TIME). Emerging studies suggest that M2 tumor-associated macrophages (TAMs), T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs) are enriched in OC. Thus, reversing the suppressive TIME is considered an ideal candidate for improving the efficiency of immunotherapy. Nanoparticles encapsulating immunoregulatory agents can regulate immunocytes and improve the TIME to boost the antitumor immune response. In addition, some nanoparticle-mediated photodynamic and photothermal therapy can directly kill tumor cells and induce tumor immunogenic cell death to activate antigen-presenting cells and promote T cell infiltration. These advantages make nanoparticles promising candidates for modulating the TIME and improving OC immunotherapy. In this review, we analyzed the composition and function of the TIME in OC and summarized the current clinical progress of OC immunotherapy. Then, we expounded on the promising advances in nanomaterial-mediated immunotherapy for modulating the TIME in OC. Finally, we discussed the obstacles and challenges in the clinical translation of this novel combination treatment regimen. We believe this resourceful strategy will open the door to effective immunotherapy of OC and benefit numerous patients.
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Affiliation(s)
| | | | | | - Jing Jing
- *Correspondence: Xiaowei Liu, ; Jing Jing,
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26
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Zhang S, Chen S, Wang Z, Li J, Yuan Y, Feng W, Li W, Chen M, Liu Y. Prognosis prediction and tumor immune microenvironment characterization based on tryptophan metabolism-related genes signature in brain glioma. Front Pharmacol 2022; 13:1061597. [PMID: 36386216 PMCID: PMC9663932 DOI: 10.3389/fphar.2022.1061597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 10/21/2022] [Indexed: 11/02/2023] Open
Abstract
Glioma is the most common malignant tumor in the central nervous system with no significant therapeutic breakthrough in recent years. Most attempts to apply immunotherapy in glioma have failed. Tryptophan and its metabolism can regulate malignant features of cancers and reshape immune microenvironment of tumors. However, the role of tryptophan metabolism in glioma remains unclear. In current study, we explored the relationships between the expression pattern of tryptophan metabolism-related genes (TrMGs) and tumor characteristics, including prognosis and tumor microenvironment of gliomas through analyzing 1,523 patients' samples from multiple public databases and our own cohort. Based on expression of TrMGs, K-means clustering analysis stratified all glioma patients into two clusters with significantly different TrMG expression patterns, clinicopathological features and immune microenvironment. Furthermore, we constructed a tryptophan metabolism-related genes signature (TrMRS) based on seven essential TrMGs to classify the patients into TrMRS low- and high-risk groups and validated the prognostic value of the TrMRS in multiple cohorts. Higher TrMRS represented for potentially more active tryptophan catabolism, which could subsequently lead to less tryptophan in tumor. The TrMRS high-risk group presented with shorter overall survival, and further analysis confirmed TrMRS as an independent prognostic factor in gliomas. The nomograms uniting TrMRS with other prognostic factors manifested with satisfactory efficacy in predicting the prognosis of glioma patients. Additionally, analyses of tumor immune landscapes demonstrated that higher TrMRS was correlated with more immune cell infiltration and "hot" immunological phenotype. TrMRS was also demonstrated to be positively correlated with the expression of multiple immunotherapy targets, including PD1 and PD-L1. Finally, the TrMRS high-risk group manifested better predicted response to immune checkpoint inhibitors. In conclusion, our study illustrated the relationships between expression pattern of TrMGs and characteristics of gliomas, and presented a novel model based on TrMRS for prognosis prediction in glioma patients. The association between TrMRS and tumor immune microenvironment of gliomas indicated an important role of tryptophan and its metabolism in reshaping immune landscape and the potential ability to guide the application of immunotherapy for gliomas.
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Affiliation(s)
- Shuxin Zhang
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Department of Head and Neck Surgery, Sichuan Cancer Hospital and Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Siliang Chen
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zhihao Wang
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Junhong Li
- Department of Neurosurgery, Chengdu Second People’s Hospital, Chengdu, Sichuan, China
| | - Yunbo Yuan
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Wentao Feng
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Wenhao Li
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Mina Chen
- State Key Laboratory of Biotherapy, Neuroscience and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China
| | - Yanhui Liu
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Lin Y, Zhou X, Ni Y, Zhao X, Liang X. Metabolic reprogramming of the tumor immune microenvironment in ovarian cancer: A novel orientation for immunotherapy. Front Immunol 2022; 13:1030831. [PMID: 36311734 PMCID: PMC9613923 DOI: 10.3389/fimmu.2022.1030831] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 09/29/2022] [Indexed: 11/17/2022] Open
Abstract
Ovarian cancer is the most lethal gynecologic tumor, with the highest mortality rate. Numerous studies have been conducted on the treatment of ovarian cancer in the hopes of improving therapeutic outcomes. Immune cells have been revealed to play a dual function in the development of ovarian cancer, acting as both tumor promoters and tumor suppressors. Increasingly, the tumor immune microenvironment (TIME) has been proposed and confirmed to play a unique role in tumor development and treatment by altering immunosuppressive and cytotoxic responses in the vicinity of tumor cells through metabolic reprogramming. Furthermore, studies of immunometabolism have provided new insights into the understanding of the TIME. Targeting or activating metabolic processes of the TIME has the potential to be an antitumor therapy modality. In this review, we summarize the composition of the TIME of ovarian cancer and its metabolic reprogramming, its relationship with drug resistance in ovarian cancer, and recent research advances in immunotherapy.
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Pallotta MT, Rossini S, Suvieri C, Coletti A, Orabona C, Macchiarulo A, Volpi C, Grohmann U. Indoleamine 2,3-dioxygenase 1 (IDO1): an up-to-date overview of an eclectic immunoregulatory enzyme. FEBS J 2022; 289:6099-6118. [PMID: 34145969 PMCID: PMC9786828 DOI: 10.1111/febs.16086] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/04/2021] [Accepted: 06/18/2021] [Indexed: 12/30/2022]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the initial rate-limiting step in the degradation of the essential amino acid tryptophan along the kynurenine pathway. When discovered more than 50 years ago, IDO1 was thought to be an effector molecule capable of mediating a survival strategy based on the deprivation of bacteria and tumor cells of the essential amino acid tryptophan. Since 1998, when tryptophan catabolism was discovered to be crucially involved in the maintenance of maternal T-cell tolerance, IDO1 has become the focus of several laboratories around the world. Indeed, IDO1 is now considered as an authentic immune regulator not only in pregnancy, but also in autoimmune diseases, chronic inflammation, and tumor immunity. However, in the last years, a bulk of new information-including structural, biological, and functional evidence-on IDO1 has come to light. For instance, we now know that IDO1 has a peculiar conformational plasticity and, in addition to a complex and highly regulated catalytic activity, is capable of performing a nonenzymic function that reprograms the expression profile of immune cells toward a highly immunoregulatory phenotype. With this state-of-the-art review, we aimed at gathering the most recent information obtained for this eclectic protein as well as at highlighting the major unresolved questions.
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Affiliation(s)
| | - Sofia Rossini
- Department of Medicine and SurgeryUniversity of PerugiaItaly
| | - Chiara Suvieri
- Department of Medicine and SurgeryUniversity of PerugiaItaly
| | - Alice Coletti
- Department of Pharmaceutical SciencesUniversity of PerugiaItaly
| | - Ciriana Orabona
- Department of Medicine and SurgeryUniversity of PerugiaItaly
| | | | - Claudia Volpi
- Department of Medicine and SurgeryUniversity of PerugiaItaly
| | - Ursula Grohmann
- Department of Medicine and SurgeryUniversity of PerugiaItaly
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Passarelli A, Pisano C, Cecere SC, Di Napoli M, Rossetti S, Tambaro R, Ventriglia J, Gherardi F, Iannacone E, Venanzio SS, Fiore F, Bartoletti M, Scognamiglio G, Califano D, Pignata S. Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer. Front Immunol 2022; 13:953115. [PMID: 36119020 PMCID: PMC9479093 DOI: 10.3389/fimmu.2022.953115] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called “kynurenine (Kyn) pathway”, which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.
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Affiliation(s)
- Anna Passarelli
- Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
- *Correspondence: Anna Passarelli,
| | - Carmela Pisano
- Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Sabrina Chiara Cecere
- Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Marilena Di Napoli
- Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Sabrina Rossetti
- Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Rosa Tambaro
- Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Jole Ventriglia
- Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Federica Gherardi
- Radiation Oncology Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Eva Iannacone
- Radiation Oncology Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | | | - Francesco Fiore
- Interventional Radiology Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Michele Bartoletti
- Medical Oncology and Cancer Prevention Unit, Department of Medical Oncology, Oncology Referral Center, Aviano, Italy
| | - Giosuè Scognamiglio
- Surgical Pathology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Daniela Califano
- Functional Genomic Unit, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
| | - Sandro Pignata
- Department of Urology and Gynecology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy
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Evaluation of Novel Inhibitors of Tryptophan Dioxygenases for Enzyme and Species Selectivity Using Engineered Tumour Cell Lines Expressing Either Murine or Human IDO1 or TDO2. Pharmaceuticals (Basel) 2022; 15:ph15091090. [PMID: 36145311 PMCID: PMC9501369 DOI: 10.3390/ph15091090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/22/2022] [Accepted: 08/22/2022] [Indexed: 11/29/2022] Open
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1) is commonly expressed by cancers as a mechanism for evading the immune system. Preclinical and clinical studies have indicated the potential of combining IDO1 inhibitors with immune therapies for the treatment of cancer, strengthening an interest in the discovery of novel dioxygenase inhibitors for reversing tumour-mediated immune suppression. To facilitate the discovery, development and investigation of novel small molecule inhibitors of IDO1 and its hepatic isozyme tryptophan dioxygenase (TDO2), murine tumour cells were engineered to selectively express either murine or human IDO1 and TDO2 for use as tools to dissect both the species specificity and isoenzyme selectivity of newly discovered inhibitors. Lewis lung carcinoma (LLTC) lines were engineered to express either murine or human IDO1 for use to test species selectivity of the novel inhibitors; in addition, GL261 glioma lines were engineered to express either human IDO1 or human TDO2 and used to test the isoenzyme selectivity of individual inhibitors in cell-based assays. The 20 most potent inhibitors against recombinant human IDO1 enzyme, discovered from a commissioned screening of 40,000 compounds in the Australian WEHI compound library, returned comparable IC50 values against murine or human IDO1 in cell-based assays using the LLTC-mIDO1 and LLTC-hIDO1 line, respectively. To test the in vivo activity of the hits, transfected lines were inoculated into syngeneic C57Bl/6 mice. Individual LLTC-hIDO1 tumours showed variable expression of human IDO1 in contrast to GL261-hIDO1 tumours which were homogenous in their IDO1 expression and were subsequently used for in vivo studies. W-0019482, the most potent IDO1 inhibitor identified from cell-based assays, reduced plasma and intratumoural ratios of kynurenine to tryptophan (K:T) and delayed the growth of subcutaneous GL261-hIDO1 tumours in mice. Synthetic modification of W-0019482 generated analogues with dual IDO1/TDO2 inhibitory activity, as well as inhibitors that were selective for either TDO2 or IDO1. These results demonstrate the versatility of W-0019482 as a lead in generating all three subclasses of tryptophan dioxygenase inhibitors which can be applied for investigating the individual roles and interactions between IDO1 and TDO2 in driving cancer-mediated immune suppression.
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Peng X, Zhao Z, Liu L, Bai L, Tong R, Yang H, Zhong L. Targeting Indoleamine Dioxygenase and Tryptophan Dioxygenase in Cancer Immunotherapy: Clinical Progress and Challenges. Drug Des Devel Ther 2022; 16:2639-2657. [PMID: 35965963 PMCID: PMC9374094 DOI: 10.2147/dddt.s373780] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/03/2022] [Indexed: 11/30/2022] Open
Abstract
Indoleamine 2.3-dioxygenases (IDO1/2) and tryptophan 2.3-dioxygenase (TDO) are the initial and rate-limiting enzymes in tryptophan metabolism, which play an essential role in mediating immunosuppression in tumor microenvironment. Accumulating evidence has indicated that both IDO1 and TDO are highly expressed in many malignant tumors, and their expression is generally associated with reduced tumor-infiltrating immune cells, increased regulatory T-cell infiltration, as well as cancer progression and poor prognosis for malignancies. A large number of IDO1 and TDO inhibitors have been screened or synthesized in the last two decades. Thus far, at least 12 antagonists targeting IDO1 and TDO have advanced to clinical trials. In this account, we conducted a comprehensive review of the development of IDO1 and TDO inhibitors in cancer immunotherapy, particularly their clinical research progress, and presented the current challenges and corresponding solutions.
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Affiliation(s)
- Xuerun Peng
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Zhipeng Zhao
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Liwen Liu
- Department of Obstetrics and Gynecology, Fengrun District People’s Hospital, Tangshan, Hebei, 063000, People’s Republic of China
| | - Lan Bai
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Rongsheng Tong
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Hao Yang
- POWERCHINA Chengdu Engineering Corporation Limited, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Lei Zhong
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
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Shi L, Duan R, Jia Q, Wu W, Zhou J, Li S, Zhang H, Xue X. Indoleamine 2,3-Dioxygenase Immune Status as a Potential Biomarker of Radioiodine Efficacy for Advanced Distant Metastatic Differentiated Thyroid Cancer. Front Oncol 2022; 12:871792. [PMID: 35924153 PMCID: PMC9339611 DOI: 10.3389/fonc.2022.871792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
PurposeHost immunity influences the impact of cancer therapy but the effect of immune status in radioiodine (RAI)-treated differentiated thyroid cancer (DTC) remains obscure. Here we investigated indoleamine 2,3-dioxygenase (IDO) activity as a biomarker of response to RAI in patients with distant metastatic DTC (dmDTC).MethodsPatients with dmDTC receiving RAI were evaluated for serum IDO activity (kynurenine and kynurenine:tryptophan ratio) at baseline and 3 months after RAI. The optimal cut-off value for these biomarkers to predict response was established by receiver operating characteristic analysis. The relationship between disease outcomes, overall survival (OS) and progression-free survival (PFS), and IDO activity levels was studied.ResultsHigher baseline kynurenine:tryptophan ratio (>2.46) was correlated with poorer RAI response as well as shorter median PFS (45 mo versus not reached, p=0.002) and OS (78 mo versus not reached, p=0.035). High baseline kynurenine:tryptophan ratio was also correlated with a reduced number of tumor-infiltrating lymphocytes. Higher post/pre-kynurenine ratio (>1.69) was associated with survival endpoints: shorter median PFS (48 mo versus not reached, p=0.002) and OS (68 mo versus not reached, p=0.010). Favorable baseline and favorable change corresponded with better PFS and OS.ConclusionsOur results suggest that RAI also alters IDO activity in dmDTC patients. IDO activity could predict progression and survival outcomes for advanced dmDTC patients. Serum IDO biomarker levels could be used to select dmDTC likely to benefit from RAI therapy, although further studies are necessary.
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Affiliation(s)
- Liang Shi
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rui Duan
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Qiong Jia
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wenyu Wu
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jianming Zhou
- Department of Nuclear Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Shaohua Li
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hao Zhang
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- *Correspondence: Xue Xue, ; Hao Zhang,
| | - Xue Xue
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Xue Xue, ; Hao Zhang,
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Atene CG, Fiorcari S, Mesini N, Alboni S, Martinelli S, Maccaferri M, Leonardi G, Potenza L, Luppi M, Maffei R, Marasca R. Indoleamine 2, 3-Dioxygenase 1 Mediates Survival Signals in Chronic Lymphocytic Leukemia via Kynurenine/Aryl Hydrocarbon Receptor-Mediated MCL1 Modulation. Front Immunol 2022; 13:832263. [PMID: 35371054 PMCID: PMC8971515 DOI: 10.3389/fimmu.2022.832263] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/21/2022] [Indexed: 01/23/2023] Open
Abstract
The indoleamine 2,3-dioxygenase 1 (IDO1) metabolic circuitry, comprising the first tryptophan (Trp) catabolite L-kynurenine (Kyn) and the aryl hydrocarbon receptor (AHR), has emerged as a mechanism of cancer immune evasion. Here, we investigated the functional role of the IDO1/Kyn/AHR axis in chronic lymphocytic leukemia (CLL). Our data show that CLL cells expressed an active form of the IDO1 enzyme and microenvironmental stimuli can positively modulate its expression. Interferon (IFN)-γ induces IDO1 expression through the Jak/STAT1 pathway and mediates Kyn production concomitantly with Trp consumption in CLL-conditioned media, while INCB018424 (ruxolitinib), a JAK1/2 inhibitor, impaired both effects. To characterize the involvement of IDO1 in leukemic cell maintenance, we overexpressed IDO1 by vector transfection measuring enhanced resistance to spontaneous apoptosis. IDO1 pro-survival influence was confirmed by treating CLL cells with Kyn, which mediated the increase of induced myeloid leukemia cell differentiation protein (MCL1). Conversely, AHR silencing or its blockade via CH-223191 improved the apoptosis of leukemic clones and mitigated MCL1 expression. Moreover, Kyn-treated CLL cells are less affected by the pro-apoptotic effect of ABT-199 (venetoclax), while CH-223191 showed synergistic/additive cytotoxicity with this drug. Lastly, targeting directly MCL1 in CLL cells with AMG-176, we abrogate the pro-survival effect of Kyn. In conclusion, our data identify IDO1/Kyn/AHR signaling as a new therapeutic target for CLL, describing for the first time its role in CLL pathobiology.
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Affiliation(s)
- Claudio Giacinto Atene
- Hematology Section, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefania Fiorcari
- Hematology Section, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicolò Mesini
- Hematology Section, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Silvia Alboni
- Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Silvia Martinelli
- Hematology Section, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
- Hematology Section, Policlinico, Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria (A.O.U.) of Modena, Modena, Italy
| | - Monica Maccaferri
- Hematology Section, Policlinico, Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria (A.O.U.) of Modena, Modena, Italy
| | - Giovanna Leonardi
- Hematology Section, Policlinico, Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria (A.O.U.) of Modena, Modena, Italy
| | - Leonardo Potenza
- Hematology Section, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
- Hematology Section, Policlinico, Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria (A.O.U.) of Modena, Modena, Italy
| | - Mario Luppi
- Hematology Section, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
- Hematology Section, Policlinico, Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria (A.O.U.) of Modena, Modena, Italy
| | - Rossana Maffei
- Hematology Section, Policlinico, Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria (A.O.U.) of Modena, Modena, Italy
| | - Roberto Marasca
- Hematology Section, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
- Hematology Section, Policlinico, Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria (A.O.U.) of Modena, Modena, Italy
- *Correspondence: Roberto Marasca,
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Odunsi K, Qian F, Lugade AA, Yu H, Geller MA, Fling SP, Kaiser JC, Lacroix AM, D’Amico L, Ramchurren N, Morishima C, Disis ML, Dennis L, Danaher P, Warren S, Van Anh N, Ravi S, Tsuji T, Rosario S, Zha W, Hutson A, Liu S, Lele S, Zsiros E, McGray AJR, Chiello J, Koya R, Chodon T, Morrison CD, Putluri V, Putluri N, Mager DE, Gunawan R, Cheever MA, Battaglia S, Matsuzaki J. Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses. Sci Transl Med 2022; 14:eabg8402. [PMID: 35294258 PMCID: PMC9311231 DOI: 10.1126/scitranslmed.abg8402] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. IDO1 inhibition resulted in efficient blockade of the kynurenine pathway of tryptophan degradation and was accompanied by a metabolic adaptation that shunted tryptophan catabolism toward the serotonin pathway. This resulted in elevated nicotinamide adenine dinucleotide (NAD+), which reduced T cell proliferation and function. Because NAD+ metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD+ on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD+-mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.
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Affiliation(s)
- Kunle Odunsi
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Feng Qian
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Amit A. Lugade
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Han Yu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Melissa A. Geller
- Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN
| | - Steven P. Fling
- Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Judith C. Kaiser
- Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Andreanne M. Lacroix
- Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Leonard D’Amico
- Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Nirasha Ramchurren
- Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Chihiro Morishima
- Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA
| | - Mary L. Disis
- Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | | | | | - Nguyen Van Anh
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY
| | - Sudharshan Ravi
- Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, NY
| | - Takemasa Tsuji
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Spencer Rosario
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Wenjuan Zha
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Alan Hutson
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Shashikant Lele
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Emese Zsiros
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - AJ Robert McGray
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Jessie Chiello
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Richard Koya
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Thinle Chodon
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Carl D. Morrison
- Department of Pathology & Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Vasanta Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Donald E. Mager
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY
- Enhanced Pharmacodynamics, LLC, Buffalo, NY
| | - Rudiyanto Gunawan
- Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, NY
| | - Martin A. Cheever
- Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Junko Matsuzaki
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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35
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Wilczyński JR, Nowak M. Cancer Immunoediting: Elimination, Equilibrium, and Immune Escape in Solid Tumors. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:1-57. [PMID: 35165859 DOI: 10.1007/978-3-030-91311-3_1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Emphasizing the dynamic processes between cancer and host immune system, the initially discovered concept of cancer immunosurveillance has been replaced by the current concept of cancer immunoediting consisting of three phases: elimination, equilibrium, and escape. Solid tumors composed of both cancer and host stromal cells are an example how the three phases of cancer immunoediting functionally evolve and how tumor shaped by the host immune system gets finally resistant phenotype. The elimination, equilibrium, and escape have been described in this chapter in details, including the role of immune surveillance, cancer dormancy, disruption of the antigen-presenting machinery, tumor-infiltrating immune cells, resistance to apoptosis, as well as the function of tumor stroma, microvesicles, exosomes, and inflammation.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
| | - Marek Nowak
- Department of Operative Gynecology and Gynecologic Oncology, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
- Department of Operative and Endoscopic Gynecology, Medical University of Lodz, Lodz, Poland
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36
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Targeting immune checkpoints in gynecologic cancer: updates & perspectives for pathologists. Mod Pathol 2022; 35:142-151. [PMID: 34493822 DOI: 10.1038/s41379-021-00882-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 12/15/2022]
Abstract
Checkpoint inhibitor-based immunotherapy is increasingly used in the treatment of gynecologic cancers, and most often targets the PD-1/PD-L1 axis. Pathologists should be familiar with the biomarkers required to determine candidacy for these treatments based on existing FDA approvals, including mismatch repair protein immunohistochemistry, microsatellite instability testing, tumor mutation burden testing, and PD-L1 immunohistochemistry. This review summarizes the rationale behind these treatments and their associated biomarkers and delivers guidance on how to utilize and readout these tests. It also introduces additional biomarkers which may provide information regarding immunotherapeutic vulnerability in the future such as neoantigen load; POLE mutation status; and immunohistochemical expression of immunosuppressive checkpoints like LAG-3, TIM-3, TIGIT, and VISTA; immune-activating checkpoints such as CD27, CD40, CD134, and CD137; enzymes such as IDO-1 and adenosine-related compounds; and MHC class I.
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37
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Obermayr E, Braicu EI, Polterauer S, Loverix L, Concin N, Woelber L, Mahner S, Sehouli J, Van Gorp T, Vergote I, Zeillinger R, Aust S. Association of a Combined Cancer Exhaustion Score with Circulating Tumor Cells and Outcome in Ovarian Cancer-A Study of the OVCAD Consortium. Cancers (Basel) 2021; 13:cancers13235865. [PMID: 34884980 PMCID: PMC8657288 DOI: 10.3390/cancers13235865] [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: 09/29/2021] [Revised: 11/19/2021] [Accepted: 11/21/2021] [Indexed: 01/22/2023] Open
Abstract
We investigated the prognostic role of systemic characteristics for cancer exhaustion and the presence of circulating tumor cells (CTCs) in primary epithelial ovarian cancer (EOC) patients. We included 185 patients in this multicenter study with a median follow-up time of 10.25 years. Albumin, c-reactive protein (CRP) and the kynurenine to tryptophan ratio (Kyn/Trp) as well as the CTC-related marker cyclophilin C (PPIC) were obtained before primary therapy and were correlated to the respective clinical and outcome data. The information provided by albumin and Kyn/Trp was integrated in a combined score for cancer exhaustion (CCES). A high CCES characterized by hypoalbuminemia and a high Kyn/Trp was associated with both decreased overall and progression-free survival, independent from other known prognostic factors in a multivariable analysis. The presence of PPIC-positive CTCs was significantly associated with a high CCES, highlighting that the interplay between the systemic microenvironment and CTCs should be considered in "liquid biopsy" biomarker assessment.
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Affiliation(s)
- Eva Obermayr
- Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria; (E.O.); (S.P.); (S.A.)
| | - Elena Ioana Braicu
- European Competence Center for Ovarian Cancer, Department of Gynecology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 13353 Berlin, Germany; (E.I.B.); (J.S.)
| | - Stephan Polterauer
- Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria; (E.O.); (S.P.); (S.A.)
| | - Liselore Loverix
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.L.); (T.V.G.); (I.V.)
| | - Nicole Concin
- Department of Obstetrics and Gynecology, Innsbruck Medical University, 6020 Innsbruck, Austria;
| | - Linn Woelber
- Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.W.); (S.M.)
| | - Sven Mahner
- Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.W.); (S.M.)
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Jalid Sehouli
- European Competence Center for Ovarian Cancer, Department of Gynecology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 13353 Berlin, Germany; (E.I.B.); (J.S.)
| | - Toon Van Gorp
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.L.); (T.V.G.); (I.V.)
| | - Ignace Vergote
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.L.); (T.V.G.); (I.V.)
| | - Robert Zeillinger
- Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria; (E.O.); (S.P.); (S.A.)
- Correspondence:
| | - Stefanie Aust
- Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria; (E.O.); (S.P.); (S.A.)
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Fucikova J, Coosemans A, Orsulic S, Cibula D, Vergote I, Galluzzi L, Spisek R. Immunological configuration of ovarian carcinoma: features and impact on disease outcome. J Immunother Cancer 2021; 9:jitc-2021-002873. [PMID: 34645669 PMCID: PMC8515436 DOI: 10.1136/jitc-2021-002873] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2021] [Indexed: 12/20/2022] Open
Abstract
Epithelial ovarian carcinoma (EOC) is a relatively rare malignancy but is the fifth-leading cause of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant disease to the peritoneum. At odds with other neoplasms, EOC is virtually insensitive to immune checkpoint inhibitors, correlating with a tumor microenvironment that exhibits poor infiltration by immune cells and active immunosuppression. Here, we comparatively summarize the humoral and cellular features of primary and metastatic EOC, comparatively analyze their impact on disease outcome, and propose measures to alter them in support of treatment sensitivity and superior patient survival.
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Affiliation(s)
- Jitka Fucikova
- Sotio Biotech, Prague, Czech Republic
- Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - An Coosemans
- Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Sandra Orsulic
- UCLA David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, USA
| | - David Cibula
- Gynecologic Oncology Center, Department of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Ignace Vergote
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University Hospital Leuven, Leuven, Belgium
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA
| | - Radek Spisek
- Sotio Biotech, Prague, Czech Republic
- Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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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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40
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Sue-A-Quan R, Patel PG, Shakfa N, Nyi MPN, Afriyie-Asante A, Kang EY, Köbel M, Koti M. Prognostic significance of T cells, PD-L1 immune checkpoint and tumour associated macrophages in clear cell carcinoma of the ovary. Gynecol Oncol 2021; 162:421-430. [PMID: 34088514 DOI: 10.1016/j.ygyno.2021.05.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/09/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To define the pre-treatment tumour immune landscape of clear cell carcinoma of the ovary (CCOC). METHODS We investigated the infiltration profiles of selected immune cell populations and immune checkpoint proteins that have been previously shown to have prognostic relevance in high grade serous carcinoma of the ovary to determine their association with clinical outcomes in CCOC patients. Using multiplex immunohistochemistry, we evaluated the density of CD3+, FoxP3+, CD8+ T cells, CD20+ B cells and expression of PD-1, PD-L1 and IDO1 immune checkpoints in a cohort of 162 CCOC tumour specimens on a tissue microarray. RESULTS Increased infiltration of CD3+ CD8- (helper T) cells, CD8+ (cytotoxic T) cells, and CD68+ macrophages significantly associated with shorter disease-free survival, recurrence-free survival and overall survival. Importantly, higher expression of PD-L1 and IDO-1 immune checkpoints was associated with better clinical outcomes. CONCLUSION Findings from our study are foundational towards the development of immune classifiers and biomarkers of response to immune checkpoint blockade therapy in CCOC.
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Affiliation(s)
- Rachel Sue-A-Quan
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
| | - Palak G Patel
- Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada; Department of Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Noor Shakfa
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
| | - May-Phyo Nyi Nyi
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Afrakoma Afriyie-Asante
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
| | - Eun Young Kang
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Martin Köbel
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Madhuri Koti
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada; Department of Obstetrics and Gynecology, Kingston Health Sciences Center, Queen's University, Kingston, Canada.
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41
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Ye X, An L, Wang X, Zhang C, Huang W, Sun C, Li R, Ma H, Wang H, Gao M. ALOX5AP Predicts Poor Prognosis by Enhancing M2 Macrophages Polarization and Immunosuppression in Serous Ovarian Cancer Microenvironment. Front Oncol 2021; 11:675104. [PMID: 34094977 PMCID: PMC8172172 DOI: 10.3389/fonc.2021.675104] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/29/2021] [Indexed: 12/20/2022] Open
Abstract
Background Serous ovarian cancer (SOC) is a highly lethal gynecological malignancy with poor prognosis. Given the importance of the immune-related tumor microenvironment (TME) in ovarian cancer, investigating tumor-immune interactions and identifying novel prognostic and therapeutic targets in SOC is a promising avenue of research. ALOX5AP (Arachidonate 5-Lipoxygenase Activating Protein) is a key enzyme in converting arachidonic acid to leukotriene: a crucial immune-modulating lipid mediator. However, the role of ALOX5AP in SOC has yet to be studied. Methods ALOX5AP expression patterns across ovarian cancer and their normal tissue counterparts were cross-checked using public microarray and RNA-seq analyses and then validated in clinical samples by qRT-PCR. Kaplan-Meier survival analysis was performed in multiple independent SOC patient cohorts. Univariate and multivariate Cox regression analysis were then employed to identify clinical risk parameters associated with survival, and a genomic-clinicopathologic nomogram was built. Gene enrichment, immune infiltration, and immunosuppressor correlation analyses were then evaluated. Results ALOX5AP mRNA levels in SOC tissues were significantly upregulated compared to normal tissues. Elevated ALOX5AP was markedly associated with poor overall survival and progression-free survival in multiple SOC patient cohorts as well as with adverse clinicopathological features, including lymphatic invasion, unsatisfactory cytoreductive surgery, rapid relapse after primary treatment, and platinum non-responsiveness. A predictive nomogram, which integrated ALOX5AP expression and two independent prognosis factors (primary therapy outcome and tumor residual), was conducted to predict the 3-year and 5-year survival rate of SOC patients. Mechanistically, functional and pathway enrichment analyses revealed that ALOX5AP was primarily involved in immune response and regulation. Further exploration demonstrated that ALOX5AP was highly expressed in the immunoreactive subtype of ovarian cancer and closely related to immunocyte infiltration, especially M2 macrophage polarization. Additionally, ALOX5AP was enriched in the C4 (lymphocyte depleted) immune subtype of SOC and associated with crucial immune-repressive receptors in the tumor microenvironment at the genomic level. Conclusions ALOX5AP expression indicates a worse survival outcome and has the potential to be utilized as a prognostic predictor for SOC patients. Given the availability of well-studied ALOX5AP inhibitors, this study has immediate clinical implications for the exploitation of ALOX5AP as an immunotherapeutic target in SOC.
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Affiliation(s)
- Xiang Ye
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Experimental Teratology of Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Limei An
- Health Management Division, Rizhao Central Hospital, Rizhao, China
| | - Xiangxiang Wang
- Department of Obstetrics and Gynecology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chenyi Zhang
- Department of Obstetrics and Gynecology, Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Wenqian Huang
- Department of Obstetrics and Gynecology, Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Chenggong Sun
- Department of Obstetrics and Gynecology, Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Rongrong Li
- Department of Obstetrics and Gynecology, Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Hanlin Ma
- Department of Obstetrics and Gynecology, Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Hongyan Wang
- Department of Obstetrics and Gynecology, Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Min Gao
- Department of Obstetrics and Gynecology, Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Jinan, China
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Li P, Xu W, Liu F, Zhu H, Zhang L, Ding Z, Liang H, Song J. The emerging roles of IDO2 in cancer and its potential as a therapeutic target. Biomed Pharmacother 2021; 137:111295. [PMID: 33550042 DOI: 10.1016/j.biopha.2021.111295] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 01/10/2021] [Accepted: 01/18/2021] [Indexed: 01/03/2023] Open
Abstract
During the past decades, tryptophan metabolism disorder was discovered to play a vital and complex role in the development of cancer. Indoleamine 2,3-dioxygenase 2 (IDO2) is one of the initial and rate-limiting enzymes of the kynurenine pathway of tryptophan catabolism. Increasing evidence indicates that IDO2 is upregulated in some tumors and plays a role in the development of cancer. In spite of the growing body of research, few reviews focused on the role of IDO2 in cancer. Here, we review the emerging knowledge on the roles of IDO2 in cancer and its potential as a therapeutic target. Firstly, the main biological features and regulatory mechanisms are reviewed, after which we focus on the expression and roles of IDO2 in cancer. Finally, we discuss the potential of IDO2 as a therapeutic target for cancer treatment.
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Affiliation(s)
- Pengcheng Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weiqi Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - He Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zeyang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Amobi-McCloud A, Muthuswamy R, Battaglia S, Yu H, Liu T, Wang J, Putluri V, Singh PK, Qian F, Huang RY, Putluri N, Tsuji T, Lugade AA, Liu S, Odunsi K. IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation. Front Immunol 2021; 12:678999. [PMID: 34025677 PMCID: PMC8136272 DOI: 10.3389/fimmu.2021.678999] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 03/30/2021] [Indexed: 11/13/2022] Open
Abstract
The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.
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Affiliation(s)
- Adaobi Amobi-McCloud
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Ravikumar Muthuswamy
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Sebastiano Battaglia
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Han Yu
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Tao Liu
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Jianmin Wang
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Vasanta Putluri
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, United States
| | - Prashant K. Singh
- Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Feng Qian
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Ruea-Yea Huang
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Nagireddy Putluri
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, United States
- Molecular and Cellular Biology, Advanced Technology Cores, Baylor College of Medicine, Houston, TX, United States
| | - Takemasa Tsuji
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
- Obstetrics and Gynecology-Gynecologic Oncology, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, United States
| | - Amit A. Lugade
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Song Liu
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Kunle Odunsi
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
- Obstetrics and Gynecology-Gynecologic Oncology, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, United States
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
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Zhao Y, Tao F, Jiang J, Chen L, Du J, Cheng X, He Q, Zhong S, Chen W, Wu X, Ou R, Xu Y, Tang KF. Tryptophan 2, 3‑dioxygenase promotes proliferation, migration and invasion of ovarian cancer cells. Mol Med Rep 2021; 23:445. [PMID: 33846800 PMCID: PMC8060793 DOI: 10.3892/mmr.2021.12084] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 03/01/2021] [Indexed: 11/24/2022] Open
Abstract
Tryptophan 2,3-dioxygenase (TDO2) is a key rate-limiting enzyme in the kynurenine pathway and promotes tumor growth and escape from immune surveillance in different types of cancer. The present study aimed to investigate whether TDO2 serves a role in the development of ovarian cancer. Reverse transcription-quantitative PCR and western blotting were used to detect the expression of TDO2 in different cell lines. The effects of TDO2 overexpression, TDO2 knockdown and TDO2 inhibitor on ovarian cancer cell proliferation, migration and invasion were determined by MTS, colony formation and Transwell assays. The expression of TDO2 in ovarian cancer tissues, normal ovarian tissues and fallopian tube tissues were analyzed using the gene expression data from The Cancer Genome Atlas and Genotype-Tissue Expression project. Immune cell infiltration in cancer tissues was evaluated using the single sample gene set enrichment analysis algorithm. The present study found that RasV12-mediated oncogenic transformation was accompanied by the upregulation of TDO2. In addition, it was demonstrated that TDO2 was upregulated in ovarian cancer tissues compared with normal ovarian tissues. TDO2 overexpression promoted proliferation, migration and invasion of ovarian cancer cells, whereas TDO2 knockdown repressed these phenotypes. Treatment with LM10, a TDO2 inhibitor, also repressed the proliferation, migration and invasion of ovarian cancer cells. The present study indicated that TDO2 can be used as a new target for the treatment of ovarian cancer.
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Affiliation(s)
- Yuemei Zhao
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Fengxing Tao
- Department of Dermato‑Venereology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Jiayu Jiang
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Lina Chen
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Jizao Du
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Xiaoxiao Cheng
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Qin He
- Department of Medical Ultrasonics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Shouhui Zhong
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Wei Chen
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Xiaoli Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Rongying Ou
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Yunsheng Xu
- Department of Dermato‑Venereology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Kai-Fu Tang
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
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Li J, Han L, Zhan S, Li R, Wang Y, Qiu T, Zhang X. 1-MT grafted carboxymethyl chitosan and its nanoparticles: Preparation, characterization and evaluation. Eur J Pharm Sci 2021; 162:105829. [PMID: 33819624 DOI: 10.1016/j.ejps.2021.105829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 11/26/2022]
Abstract
This work aims to synthesize two novel 1-MT (1-Methyl-DL-tryptophan) grafted CMCS (carboxymethyl chitosan) polymer prodrugs CMCS-amido-1-MT and CMCS-ester-1-MT, and to further manufacture their nanoparticles for potential biomedical applications. The polymeric prodrugs are prepared by three-step chemical synthesis. The chemical structure of drugs is confirmed by FTIR and 1H-NMR. The drug loadings of the CMCS-amido-1-MT NPs and CMCS-ester-1-MT NPs are 11.43% and 10.18%, respectively. The surface morphology of the nanoparticles is spherical or nearly spherical, while the surface is smooth and the size distribution is uniform. The average particle size is both about 200 nm, while the polydispersity index is both about 0.15. The nanoparticles have a negative charge on the surface. The particle size and its distribution change little, when the two nanoparticles are tested in the simulated blood pH environment for 7 days. However, only the CMCS-ester-1-MT nanoparticles are pH-sensitive. The cell toxicity of the CMCS-ester-1-MT nanoparticles and the original drug are both in a dose- and time-dependent manner, while the nanoparticles enter cells by endocytosis. In ECA109 cells, the CMCS-ester-1-MT nanoparticles and the original drug both induce the apoptosis. CMCS-ester-1-MT NPs can activate the ATF4/CHOP pathway in endoplasmic reticulum stress, and achieve cancer suppression through mitochondrial-related apoptosis.
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Affiliation(s)
- Jiaming Li
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China
| | - Lei Han
- School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, PR China; State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China
| | - Siwen Zhan
- Department of Pharmaceutical Engineering, School of Chemical Engineering, Wuhan University of Technology, Wuhan 430070, China
| | - Ran Li
- China Tobacco Hubei Industrial Co., Ltd., China
| | - Yaowen Wang
- Department of Pharmaceutical Engineering, School of Chemical Engineering, Wuhan University of Technology, Wuhan 430070, China
| | - Tong Qiu
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China; Biomedical Materials and Engineering Research Center of Hubei Province, Wuhan 430070, China.
| | - Xueqiong Zhang
- Department of Pharmaceutical Engineering, School of Chemical Engineering, Wuhan University of Technology, Wuhan 430070, China.
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Abdulla M, Alexsson A, Sundström C, Ladenvall C, Mansouri L, Lindskog C, Berglund M, Cavelier L, Enblad G, Hollander P, Amini RM. PD-L1 and IDO1 are potential targets for treatment in patients with primary diffuse large B-cell lymphoma of the CNS. Acta Oncol 2021; 60:531-538. [PMID: 33579170 DOI: 10.1080/0284186x.2021.1881161] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, as well as Indoleamine 2,3-deoxygenase (IDO1) can be expressed both by tumor and microenvironmental cells and are crucial for tumor immune escape. We aimed to evaluate the role of PD-1, its ligands and IDO1 in a cohort of patients with primary diffuse large B-cell lymphoma of the CNS (PCNSL). MATERIAL AND METHODS Tissue microarrays (TMAs) were constructed in 45 PCNSL cases. RNA extraction from whole tissue sections and RNA sequencing were successfully performed in 33 cases. Immunohistochemical stainings for PD-1, PD-L1/paired box protein 5 (PAX-5), PD-L2/PAX-5 and IDO1, and Epstein-Barr virus encoding RNA (EBER) in situ hybridization were analyzed. RESULTS High proportions of PD-L1 and PD-L2 positive tumor cells were observed in 11% and 9% of cases, respectively. High proportions of PD-L1 and PD-L2 positive leukocytes were observed in 55% and 51% of cases, respectively. RNA sequencing revealed that gene expression of IDO1 was high in patients with high proportion of PD-L1 positive leukocytes (p = .01). Protein expression of IDO1 in leukocytes was detected in 14/45 cases, in 79% of these cases a high proportion of PD-L1 positive leukocytes was observed. Gene expression of IDO1 was high in EBER-positive cases (p = .0009) and protein expression of IDO1 was detected in five of six EBER-positive cases. CONCLUSION Our study shows a significant association between gene and protein expression of IDO1 and protein expression of PD-L1 in the tumor microenvironment of PCNSL, possibly of importance for prediction of response to immunotherapies.
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Affiliation(s)
- Maysaa Abdulla
- Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University and University Hospital, Uppsala, Sweden
| | - Andrei Alexsson
- Clinical Genomics Uppsala, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Christer Sundström
- Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University and University Hospital, Uppsala, Sweden
| | - Claes Ladenvall
- Clinical Genomics Uppsala, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Larry Mansouri
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Mattias Berglund
- Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Lucia Cavelier
- Clinical Genomics Uppsala, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Gunilla Enblad
- Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Peter Hollander
- Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University and University Hospital, Uppsala, Sweden
| | - Rose-Marie Amini
- Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University and University Hospital, Uppsala, Sweden
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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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Yao Y, Liang H, Fang X, Zhang S, Xing Z, Shi L, Kuang C, Seliger B, Yang Q. What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:60. [PMID: 33557876 PMCID: PMC7869231 DOI: 10.1186/s13046-021-01847-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 01/14/2021] [Indexed: 12/14/2022]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed.
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Affiliation(s)
- Yu Yao
- State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, 200438, Shanghai, China
| | - Heng Liang
- State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, 200438, Shanghai, China
| | - Xin Fang
- State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, 200438, Shanghai, China
| | - Shengnan Zhang
- State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, 200438, Shanghai, China
| | - Zikang Xing
- State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, 200438, Shanghai, China
| | - Lei Shi
- State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, 200438, Shanghai, China
| | - Chunxiang Kuang
- Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092, Shanghai, China
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Straße 2, 06112, Halle (Saale), Germany
| | - Qing Yang
- State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, 200438, Shanghai, China.
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Ala M. The footprint of kynurenine pathway in every cancer: a new target for chemotherapy. Eur J Pharmacol 2021; 896:173921. [PMID: 33529725 DOI: 10.1016/j.ejphar.2021.173921] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/08/2021] [Accepted: 01/26/2021] [Indexed: 02/06/2023]
Abstract
Treatment of cancers has always been a challenge for physicians. Typically, several groups of anti-cancer medications are needed for effective management of an invasive and metastatic cancer. Recently, therapeutic potentiation of immune system markedly improved treatment of cancers. Kynurenine pathway has an interwoven correlation with immune system. Kynurenine promotes T Reg (regulatory) differentiation, which leads to increased production of anti-inflammatory cytokines and suppression of cytotoxic activity of T cells. Overactivation of kynurenine pathway in cancers provides an immunologically susceptible microenvironment for mutant cells to survive and invade surrounding tissues. Interestingly, kynurenine pathway vigorously interacts with other molecular pathways involved in tumorigenesis. For instance, kynurenine pathway interacts with phospoinosisitide-3 kinase (PI3K), extracellular signal-regulated kinase (ERK), Wnt/β-catenin, P53, bridging integrator 1 (BIN-1), cyclooxygenase 2 (COX-2), cyclin-dependent kinase (CDK) and collagen type XII α1 chain (COL12A1). Overactivation of kynurenine pathway, particularly overactivation of indoleamine 2,3-dioxygenase (IDO) predicts poor prognosis of several cancers such as gastrointestinal cancers, gynecological cancers, hematologic malignancies, breast cancer, lung cancer, glioma, melanoma, prostate cancer and pancreatic cancer. Furthermore, kynurenine increases the invasion, metastasis and chemoresistance of cancer cells. Recently, IDO inhibitors entered clinical trials and successfully passed their safety tests and showed promising therapeutic efficacy for cancers such as melanoma, brain cancer, renal cell carcinoma, prostate cancer and pancreatic cancer. However, a phase III trial of epacadostat, an IDO inhibitor, could not increase the efficacy of treatment with pembrolizumab for melanoma. In this review the expanding knowledge towards kynurenine pathway and its application in each cancer is discussed separately.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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50
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Grobben Y, de Man J, van Doornmalen AM, Muller M, Willemsen-Seegers N, Vu-Pham D, Mulder WR, Prinsen MBW, de Wit J, Sterrenburg JG, van Cauter F, den Ouden JE, van Altena AM, Massuger LF, Uitdehaag JCM, Buijsman RC, Zaman GJR. Targeting Indoleamine 2,3-Dioxygenase in Cancer Models Using the Novel Small Molecule Inhibitor NTRC 3883-0. Front Immunol 2021; 11:609490. [PMID: 33584686 PMCID: PMC7876453 DOI: 10.3389/fimmu.2020.609490] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/10/2020] [Indexed: 12/19/2022] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO1) is a key regulator of immune suppression by catalyzing the oxidation of L-tryptophan. IDO1 expression has been related to poor prognosis in several cancers and to resistance to checkpoint immunotherapies. We describe the characterization of a novel small molecule IDO1 inhibitor, NTRC 3883-0, in a panel of biochemical and cell-based assays, and various cancer models. NTRC 3883-0 released the inhibitory effect of IDO1 on CD8-positive T cell proliferation in co-cultures of IDO1-overexpressing cells with healthy donor lymphocytes, demonstrating its immune modulatory activity. In a syngeneic mouse model using IDO1-overexpressing B16F10 melanoma cells, NTRC 3883-0 effectively counteracted the IDO1-induced modulation of L-tryptophan and L-kynurenine levels, demonstrating its in vivo target modulation. Finally, we studied the expression and activity of IDO1 in primary cell cultures established from the malignant ascites of ovarian cancer patients. In these cultures, IDO1 expression was induced upon stimulation with IFNγ, and its activity could be inhibited by NTRC 3883-0. Based on these results, we propose the use of ascites cell-based functional assays for future patient stratification. Our results are discussed in light of the recent discontinuation of clinical trials of more advanced IDO1 inhibitors and the reconsideration of IDO1 as a valid drug target.
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Affiliation(s)
- Yvonne Grobben
- Netherlands Translational Research Center B.V., Oss, Netherlands
| | - Jos de Man
- Netherlands Translational Research Center B.V., Oss, Netherlands
| | | | - Michelle Muller
- Netherlands Translational Research Center B.V., Oss, Netherlands
| | | | - Diep Vu-Pham
- Netherlands Translational Research Center B.V., Oss, Netherlands
| | | | | | - Joeri de Wit
- Netherlands Translational Research Center B.V., Oss, Netherlands
| | | | - Freek van Cauter
- Netherlands Translational Research Center B.V., Oss, Netherlands
| | - Judith E. den Ouden
- Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Anne M. van Altena
- Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Leon F. Massuger
- Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands
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