|
1
|
Viel S, Vivier E, Walzer T, Marçais A. Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer. Nat Rev Drug Discov 2025; 24:190-208. [PMID: 39668206 DOI: 10.1038/s41573-024-01098-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 12/14/2024]
Abstract
The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.
Collapse
Affiliation(s)
- Sébastien Viel
- Plateforme de Biothérapie et de Production de Médicaments de Thérapie Innovante, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Eric Vivier
- Innate Pharma Research Laboratories, Innate Pharma, Marseille, France
- Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
- APHM, Hôpital de la Timone, Marseille, France
- Paris Saclay Cancer Cluster, Villejuif, France
- Université Paris-Saclay, Gustave Roussy, Inserm, Prédicteurs moléculaires et nouvelles cibles en oncologie, Villejuif, France
| | - Thierry Walzer
- CIRI, Centre International de Recherche en Infectiologie, (Team Lyacts), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS UMR5308 ENS de Lyon, Lyon, France
| | - Antoine Marçais
- CIRI, Centre International de Recherche en Infectiologie, (Team Lyacts), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS UMR5308 ENS de Lyon, Lyon, France.
| |
Collapse
|
|
2
|
Zhou Y, Lou J, Tian Y, Ding J, Wang X, Tang B. How lactate affects immune strategies in lymphoma. Front Mol Biosci 2024; 11:1480884. [PMID: 39464313 PMCID: PMC11502318 DOI: 10.3389/fmolb.2024.1480884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/30/2024] [Indexed: 10/29/2024] Open
Abstract
Tumor cells undergo metabolic reprogramming through shared pathways, resulting in a hypoxic, acidic, and highly permeable internal tumor microenvironment (TME). Lactate, once only regarded as a waste product of glycolysis, has an inseparable dual role with tumor immunity. It can not only provide a carbon source for immune cells to enhance immunity but also help the immune escape through a variety of ways. Lymphoma also depends on the proliferation signal of TME. This review focuses on the dynamic process of lactate metabolism and immune function changes in lymphoma and aims to comprehensively summarize and explore which genes, transcription factors, and pathways affect the biological changes and functions of immune cells. To deeply understand the complex and multifaceted role of lactate metabolism and immunity in lymphoma, the combination of lactate targeted therapy and classical immunotherapy will be a promising development direction in the future.
Collapse
Affiliation(s)
- Yuehan Zhou
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinzhan Lou
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuqin Tian
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinlei Ding
- Department of Thoracic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaobo Wang
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bo Tang
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| |
Collapse
|
|
3
|
Guerrero JA, Klysz DD, Chen Y, Malipatlolla M, Lone J, Fowler C, Stuani L, May A, Bashti M, Xu P, Huang J, Michael B, Contrepois K, Dhingra S, Fisher C, Svensson KJ, Davis KL, Kasowski M, Feldman SA, Sotillo E, Mackall CL. GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency. Nat Commun 2024; 15:8658. [PMID: 39370422 PMCID: PMC11456602 DOI: 10.1038/s41467-024-52666-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 09/18/2024] [Indexed: 10/08/2024] Open
Abstract
The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.
Collapse
Affiliation(s)
- Justin A Guerrero
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Dorota D Klysz
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Yiyun Chen
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Meena Malipatlolla
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Jameel Lone
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Carley Fowler
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Lucille Stuani
- Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Audre May
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Malek Bashti
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Peng Xu
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Jing Huang
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Basil Michael
- Metabolic Health Center, Stanford University School of Medicine, Stanford, CA, USA
| | - Kévin Contrepois
- Metabolic Health Center, Stanford University School of Medicine, Stanford, CA, USA
| | - Shaurya Dhingra
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Chris Fisher
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Katrin J Svensson
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Kara L Davis
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
- Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Maya Kasowski
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
- Department of Genetics, Stanford University, Stanford, CA, USA
- Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford University, Stanford, CA, USA
- Division of Bone Marrow Transplant-Cell Therapy, Dept of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Steven A Feldman
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA
| | - Elena Sotillo
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA.
| | - Crystal L Mackall
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA.
- Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
- Division of Bone Marrow Transplant-Cell Therapy, Dept of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
| |
Collapse
|
|
4
|
Einhaus J, Gaudilliere DK, Hedou J, Feyaerts D, Ozawa MG, Sato M, Ganio EA, Tsai AS, Stelzer IA, Bruckman KC, Amar JN, Sabayev M, Bonham TA, Gillard J, Diop M, Cambriel A, Mihalic ZN, Valdez T, Liu SY, Feirrera L, Lam DK, Sunwoo JB, Schürch CM, Gaudilliere B, Han X. Spatial subsetting enables integrative modeling of oral squamous cell carcinoma multiplex imaging data. iScience 2023; 26:108486. [PMID: 38125025 PMCID: PMC10730356 DOI: 10.1016/j.isci.2023.108486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 11/01/2023] [Accepted: 11/16/2023] [Indexed: 12/23/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC), a prevalent and aggressive neoplasm, poses a significant challenge due to poor prognosis and limited prognostic biomarkers. Leveraging highly multiplexed imaging mass cytometry, we investigated the tumor immune microenvironment (TIME) in OSCC biopsies, characterizing immune cell distribution and signaling activity at the tumor-invasive front. Our spatial subsetting approach standardized cellular populations by tissue zone, improving feature reproducibility and revealing TIME patterns accompanying loss-of-differentiation. Employing a machine-learning pipeline combining reliable feature selection with multivariable modeling, we achieved accurate histological grade classification (AUC = 0.88). Three model features correlated with clinical outcomes in an independent cohort: granulocyte MAPKAPK2 signaling at the tumor front, stromal CD4+ memory T cell size, and the distance of fibroblasts from the tumor border. This study establishes a robust modeling framework for distilling complex imaging data, uncovering sentinel characteristics of the OSCC TIME to facilitate prognostic biomarkers discovery for recurrence risk stratification and immunomodulatory therapy development.
Collapse
Affiliation(s)
- Jakob Einhaus
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Dyani K. Gaudilliere
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Julien Hedou
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Dorien Feyaerts
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Michael G. Ozawa
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Masaki Sato
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Edward A. Ganio
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Amy S. Tsai
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Ina A. Stelzer
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Karl C. Bruckman
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Jonas N. Amar
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Maximilian Sabayev
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Thomas A. Bonham
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Joshua Gillard
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Maïgane Diop
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Amelie Cambriel
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Zala N. Mihalic
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Tulio Valdez
- Division of Pediatrics, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA, USA
| | - Stanley Y. Liu
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
- Division of Sleep Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA, USA
| | - Leticia Feirrera
- Department of Oral and Maxillofacial Surgery, University of the Pacific, Arthur A. Dugoni School of Dentistry, San Francisco, CA, USA
| | - David K. Lam
- Department of Oral and Maxillofacial Surgery, University of the Pacific, Arthur A. Dugoni School of Dentistry, San Francisco, CA, USA
| | - John B. Sunwoo
- Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA, USA
| | - Christian M. Schürch
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Brice Gaudilliere
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiaoyuan Han
- Department of Biomedical Sciences, University of the Pacific, Arthur A. Dugoni School of Dentistry, San Francisco, CA, USA
| |
Collapse
|
|
5
|
Heaton AR, Rehani PR, Hoefges A, Lopez AF, Erbe AK, Sondel PM, Skala MC. Single cell metabolic imaging of tumor and immune cells in vivo in melanoma bearing mice. Front Oncol 2023; 13:1110503. [PMID: 37020875 PMCID: PMC10067577 DOI: 10.3389/fonc.2023.1110503] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 03/02/2023] [Indexed: 03/22/2023] Open
Abstract
Introduction Metabolic reprogramming of cancer and immune cells occurs during tumorigenesis and has a significant impact on cancer progression. Unfortunately, current techniques to measure tumor and immune cell metabolism require sample destruction and/or cell isolations that remove the spatial context. Two-photon fluorescence lifetime imaging microscopy (FLIM) of the autofluorescent metabolic coenzymes nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD) provides in vivo images of cell metabolism at a single cell level. Methods Here, we report an immunocompetent mCherry reporter mouse model for immune cells that express CD4 either during differentiation or CD4 and/or CD8 in their mature state and perform in vivo imaging of immune and cancer cells within a syngeneic B78 melanoma model. We also report an algorithm for single cell segmentation of mCherry-expressing immune cells within in vivo images. Results We found that immune cells within B78 tumors exhibited decreased FAD mean lifetime and an increased proportion of bound FAD compared to immune cells within spleens. Tumor infiltrating immune cell size also increased compared to immune cells from spleens. These changes are consistent with a shift towards increased activation and proliferation in tumor infiltrating immune cells compared to immune cells from spleens. Tumor infiltrating immune cells exhibited increased FAD mean lifetime and increased protein-bound FAD lifetime compared to B78 tumor cells within the same tumor. Single cell metabolic heterogeneity was observed in both immune and tumor cells in vivo. Discussion This approach can be used to monitor single cell metabolic heterogeneity in tumor cells and immune cells to study promising treatments for cancer in the native in vivo context.
Collapse
Affiliation(s)
- Alexa R. Heaton
- Morgridge Institute for Research, Madison, WI, United States
- Department of Human Oncology, University of Wisconsin, Madison, WI, United States
| | - Peter R. Rehani
- Morgridge Institute for Research, Madison, WI, United States
| | - Anna Hoefges
- Department of Human Oncology, University of Wisconsin, Madison, WI, United States
| | - Angelica F. Lopez
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, United States
| | - Amy K. Erbe
- Department of Human Oncology, University of Wisconsin, Madison, WI, United States
| | - Paul M. Sondel
- Department of Human Oncology, University of Wisconsin, Madison, WI, United States
- Department of Pediatrics, University of Wisconsin, Madison, WI, United States
| | - Melissa C. Skala
- Morgridge Institute for Research, Madison, WI, United States
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, United States
| |
Collapse
|
|
6
|
Zeng X, Wang YP, Man CH. Metabolism in Hematopoiesis and Its Malignancy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1442:45-64. [PMID: 38228958 DOI: 10.1007/978-981-99-7471-9_4] [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: 01/18/2024]
Abstract
Hematopoietic stem cells (HSCs) are multipotent stem cells that can self-renew and generate all blood cells of different lineages. The system is under tight control in order to maintain a precise equilibrium of the HSC pool and the effective production of mature blood cells to support various biological activities. Cell metabolism can regulate different molecular activities, such as epigenetic modification and cell cycle regulation, and subsequently affects the function and maintenance of HSC. Upon malignant transformation, oncogenic drivers in malignant hematopoietic cells can remodel the metabolic pathways for supporting the oncogenic growth. The dysregulation of metabolism results in oncogene addiction, implying the development of malignancy-specific metabolism-targeted therapy. In this chapter, we will discuss the significance of different metabolic pathways in hematopoiesis, specifically, the distinctive metabolic dependency in hematopoietic malignancies and potential metabolic therapy.
Collapse
Affiliation(s)
- Xiaoyuan Zeng
- Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Yi-Ping Wang
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Cheuk-Him Man
- Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| |
Collapse
|
|
7
|
Jin P, Bai M, Liu J, Yu J, Meng X. Tumor metabolic and secondary lymphoid organ metabolic markers on 18F-fludeoxyglucose positron emission tomography predict prognosis of immune checkpoint inhibitors in advanced lung cancer. Front Immunol 2022; 13:1004351. [PMID: 36341372 PMCID: PMC9634068 DOI: 10.3389/fimmu.2022.1004351] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/06/2022] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND The purpose of this study was to investigate the predictive value of tumor metabolic parameters in combination with secondary lymphoid metabolic parameters on positron emission tomography (PET)/computed tomography (CT) for immune checkpoint inhibitor (ICI) prognosis in advanced lung cancer. METHODS This study retrospectively included 125 patients who underwent 18F-fludeoxyglucose (FDG) PET/CT before ICI therapy, including 41 patients who underwent a second PET/CT scan during ICI treatment. The measured PET/CT parameters included tumor metabolism parameters [maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), total lesion glycolysis (TLG), and total metabolic tumor volume (TMTV)] and secondary lymphoid organ metabolism parameters [spleen-to-liver SUVmax ratio (SLR) and bone marrow-to-liver SUVmax ratio (BLR)]. The correlation of PET/CT metabolic parameters with early ICI treatment response, progression-free survival (PFS), and overall survival (OS) was analyzed. RESULTS Within a median follow-up of 28.7 months, there were 44 responders and 81 non-responders. The median PFS was 8.6 months (95% confidence interval (CI): 5.872-11.328), and the median OS was 20.4 months (95% CI: 15.526-25.274). Pretreatment tumor metabolic parameters were not associated with early treatment responses. The high bone marrow metabolism (BLR >1.03) was significantly associated with a shorter PFS (p = 0.008). Patients with a high TMTV (>168 mL) and high spleen metabolism (SLR >1.08) had poor OS (p = 0.019 and p = 0.018, respectively). Among the 41 patients who underwent a second PET/CT scan, the ΔSUVmax was significantly lower (p = 0.01) and the SLR was significantly higher (p = 0.0086) in the responders. Populations with low-risk characteristics (low TMTV, low SLR, and ΔSLR > 0) had the longest survival times. CONCLUSION High pretreatment TMTV and SLR are associated with poor OS, and increased spleen metabolism after ICI therapy predicts treatment benefit. This indicates that the combination of tumor and spleen metabolic parameters is a valuable prognostic strategy.
Collapse
Affiliation(s)
- Peng Jin
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Menglin Bai
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Department of Radiation Oncology, Shandong University Cancer Center, Jinan, China
| | - Jie Liu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jinming Yu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Department of Radiation Oncology, Shandong University Cancer Center, Jinan, China
- Research Unit of Radiation Oncology, Chinese Academy of Medical Sciences, Jinan, China
| | - Xue Meng
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Department of Radiation Oncology, Shandong University Cancer Center, Jinan, China
| |
Collapse
|
|
8
|
Guerau-de-Arellano M, Piedra-Quintero ZL, Tsichlis PN. Akt isoforms in the immune system. Front Immunol 2022; 13:990874. [PMID: 36081513 PMCID: PMC9445622 DOI: 10.3389/fimmu.2022.990874] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 08/04/2022] [Indexed: 11/29/2022] Open
Abstract
Akt is a PI3K-activated serine-threonine kinase that exists in three distinct isoforms. Akt's expression in most immune cells, either at baseline or upon activation, reflects its importance in the immune system. While Akt is most highly expressed in innate immune cells, it plays crucial roles in both innate and adaptive immune cell development and/or effector functions. In this review, we explore what's known about the role of Akt in innate and adaptive immune cells. Wherever possible, we discuss the overlapping and distinct role of the three Akt isoforms, namely Akt1, Akt2, and Akt3, in immune cells.
Collapse
Affiliation(s)
- Mireia Guerau-de-Arellano
- School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, United States,Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, United States,Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States,Department of Neuroscience, The Ohio State University, Columbus, OH, United States,The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States,*Correspondence: Mireia Guerau-de-Arellano,
| | - Zayda L. Piedra-Quintero
- School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
| | - Philip N. Tsichlis
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States,Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, United States
| |
Collapse
|
|
9
|
Qin Y, Gao C, Luo J. Metabolism Characteristics of Th17 and Regulatory T Cells in Autoimmune Diseases. Front Immunol 2022; 13:828191. [PMID: 35281063 PMCID: PMC8913504 DOI: 10.3389/fimmu.2022.828191] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/07/2022] [Indexed: 12/12/2022] Open
Abstract
The abnormal number and functional deficiency of immune cells are the pathological basis of various diseases. Recent years, the imbalance of Th17/regulatory T (Treg) cell underlies the occurrence and development of inflammation in autoimmune diseases (AID). Currently, studies have shown that material and energy metabolism is essential for maintaining cell survival and normal functions and the altered metabolic state of immune cells exists in a variety of AID. This review summarizes the biology and functions of Th17 and Treg cells in AID, with emphasis on the advances of the roles and regulatory mechanisms of energy metabolism in activation, differentiation and physiological function of Th17 and Treg cells, which will facilitate to provide targets for the treatment of immune-mediated diseases.
Collapse
Affiliation(s)
- Yan Qin
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chong Gao
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Jing Luo
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Jing Luo,
| |
Collapse
|
|
10
|
Liu F, Gao Y, Xu B, Xiong S, Yi S, Sun J, Chen Z, Liu X, Li Y, Lin Y, Wen Y, Qin Y, Yang S, Li H, Tejasvi T, Tsoi L, Tu P, Ren X, Wang Y. PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma. Blood 2022; 139:554-571. [PMID: 34582557 PMCID: PMC8893588 DOI: 10.1182/blood.2021012091] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 09/07/2021] [Indexed: 01/29/2023] Open
Abstract
Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergo large-cell transformation (LCT) in the late stage, manifesting aggressive behavior, resistance to treatments, and poor prognosis, but the mechanisms involved remain unclear. To identify the molecular driver of LCT, we collected tumor samples from 133 MF patients and performed whole-transcriptome sequencing on 49 advanced-stage MF patients, followed by integrated copy number inference and genomic hybridization. Tumors with LCT showed unique transcriptional programs and enriched expressions of genes at chr7q. Paternally expressed gene 10 (PEG10), an imprinted gene at 7q21.3, was ectopically expressed in malignant T cells from LCT, driven by 7q21.3 amplification. Mechanistically, aberrant PEG10 expression increased cell size, promoted cell proliferation, and conferred treatment resistance by a PEG10/KLF2/NF-κB axis in in vitro and in vivo models. Pharmacologically targeting PEG10 reversed the phenotypes of proliferation and treatment resistance in LCT. Our findings reveal new molecular mechanisms underlying LCT and suggest that PEG10 inhibition may serve as a promising therapeutic approach in late-stage aggressive T-cell lymphoma.
Collapse
MESH Headings
- Animals
- Apoptosis Regulatory Proteins/genetics
- Cell Line, Tumor
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- DNA-Binding Proteins/genetics
- Female
- Gene Amplification
- Gene Expression Regulation, Neoplastic
- Genomic Imprinting
- Humans
- Lymphoma, T-Cell, Cutaneous/genetics
- Lymphoma, T-Cell, Cutaneous/pathology
- Mice, Inbred NOD
- Mice, SCID
- Mycosis Fungoides/genetics
- Mycosis Fungoides/pathology
- RNA-Binding Proteins/genetics
- Skin Neoplasms/genetics
- Skin Neoplasms/pathology
- Mice
Collapse
Affiliation(s)
- Fengjie Liu
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Yumei Gao
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Bufang Xu
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Shan Xiong
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Shengguo Yi
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Jingru Sun
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Zhuojing Chen
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Xiangjun Liu
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Yingyi Li
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Yuchieh Lin
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Yujie Wen
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Yao Qin
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Shuxia Yang
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Hang Li
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Trilokraj Tejasvi
- Department of Dermatology, University of Michigan, Ann Arbor, MI; and
| | - Lam Tsoi
- Department of Dermatology, University of Michigan, Ann Arbor, MI; and
| | - Ping Tu
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| | - Xianwen Ren
- Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100034, China
| | - Yang Wang
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China
| |
Collapse
|
|
11
|
The Modes of Dysregulation of the Proto-Oncogene T-Cell Leukemia/Lymphoma 1A. Cancers (Basel) 2021; 13:cancers13215455. [PMID: 34771618 PMCID: PMC8582492 DOI: 10.3390/cancers13215455] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/26/2021] [Accepted: 10/28/2021] [Indexed: 11/19/2022] Open
Abstract
Simple Summary T-cell leukemia/lymphoma 1A (TCL1A) is a proto-oncogene that is mainly expressed in embryonic and fetal tissues, as well as in some lymphatic cells. It is frequently overexpressed in a variety of T- and B-cell lymphomas and in some solid tumors. In chronic lymphocytic leukemia and in T-prolymphocytic leukemia, TCL1A has been implicated in the pathogenesis of these conditions, and high-level TCL1A expression correlates with more aggressive disease characteristics and poorer patient survival. Despite the modes of TCL1A (dys)regulation still being incompletely understood, there are recent advances in understanding its (post)transcriptional regulation. This review summarizes the current concepts of TCL1A’s multi-faceted modes of regulation. Understanding how TCL1A is deregulated and how this can lead to tumor initiation and sustenance can help in future approaches to interfere in its oncogenic actions. Abstract Incomplete biological concepts in lymphoid neoplasms still dictate to a large extent the limited availability of efficient targeted treatments, which entertains the mostly unsatisfactory clinical outcomes. Aberrant expression of the embryonal and lymphatic TCL1 family of oncogenes, i.e., the paradigmatic TCL1A, but also TML1 or MTCP1, is causally implicated in T- and B-lymphocyte transformation. TCL1A also carries prognostic information in these particular T-cell and B-cell tumors. More recently, the TCL1A oncogene has been observed also in epithelial tumors as part of oncofetal stemness signatures. Although the concepts on the modes of TCL1A dysregulation in lymphatic neoplasms and solid tumors are still incomplete, there are recent advances in defining the mechanisms of its (de)regulation. This review presents a comprehensive overview of TCL1A expression in tumors and the current understanding of its (dys)regulation via genomic aberrations, epigenetic modifications, or deregulation of TCL1A-targeting micro RNAs. We also summarize triggers that act through such transcriptional and translational regulation, i.e., altered signals by the tumor microenvironment. A refined mechanistic understanding of these modes of dysregulations together with improved concepts of TCL1A-associated malignant transformation can benefit future approaches to specifically interfere in TCL1A-initiated or -driven tumorigenesis.
Collapse
|
|
12
|
Hatzioannou A, Boumpas A, Papadopoulou M, Papafragkos I, Varveri A, Alissafi T, Verginis P. Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle. Front Immunol 2021; 12:731947. [PMID: 34539668 PMCID: PMC8446642 DOI: 10.3389/fimmu.2021.731947] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/18/2021] [Indexed: 01/08/2023] Open
Abstract
Regulatory T (Treg) cells, possess a strategic role in the maintenance of immune homeostasis, and their function has been closely linked to development of diverse pathologies including autoimmunity and cancer. Comprehensive studies in various disease contexts revealed an increased plasticity as a characteristic of Treg cells. Although Treg cell plasticity comes in various flavors, the major categories enclose the loss of Foxp3 expression, which is the master regulator of Treg cell lineage, giving rise to “ex-Treg” cells and the “fragile” Treg cells in which FOXP3 expression is retained but accompanied by the engagement of an inflammatory program and attenuation of the suppressive activity. Treg cell plasticity possess a tremendous therapeutic potential either by inducing Treg cell de-stabilization to promote anti-tumor immunity, or re-enforcing Treg cell stability to attenuate chronic inflammation. Herein, we review the literature on the Treg cell plasticity with lessons learned in autoimmunity and cancer and discuss challenges and open questions with potential therapeutic implications.
Collapse
Affiliation(s)
- Aikaterini Hatzioannou
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Athina Boumpas
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Miranta Papadopoulou
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Iosif Papafragkos
- Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece.,Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
| | - Athina Varveri
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Themis Alissafi
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Panayotis Verginis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.,Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece.,Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
| |
Collapse
|
|
13
|
Aria H, Ghaedrahmati F, Ganjalikhani-Hakemi M. Cutting edge: Metabolic immune reprogramming, reactive oxygen species, and cancer. J Cell Physiol 2021; 236:6168-6189. [PMID: 33561318 DOI: 10.1002/jcp.30303] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 01/09/2021] [Accepted: 01/19/2021] [Indexed: 02/05/2023]
Abstract
A recently proposed term "immunometabolism" points to the functional intracellular metabolic changes that occur within different immune cells. Recent findings suggest that immune responses can be determined by the metabolic status of immune cells and metabolic reprogramming is an important feature of immune cell activation. Metabolic reprogramming is also well known for cancer cells and has been suggested as a major sign of cancer progression. Metabolic reprogramming of immune cells is also seen in the tumor microenvironment. In the past decade, immunometabolism has progressively become an extraordinarily vibrant and productive area of study in immunology because of its importance for immunotherapy. Understanding the immunometabolic situation of T cells and other immune cells along with the metabolic behavior of cancer cells can help us design new therapeutic approaches against cancers. Here, we have the aim to review the cutting-edge findings on the immunometabolic situation in immune and tumor cells. We discuss new findings on signaling pathways during metabolic reprogramming, its regulation, and the participation of reactive oxygen species in these processes.
Collapse
Affiliation(s)
- Hamid Aria
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farhoodeh Ghaedrahmati
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | |
Collapse
|
|
14
|
Guo Q, Chu Y, Li H, Shi D, Lin L, Lan W, Wu D. Dickkopf-related protein 3 alters aerobic glycolysis in pancreatic cancer BxPC-3 cells, promoting CD4 + T-cell activation and function. Eur J Med Res 2021; 26:93. [PMID: 34391478 PMCID: PMC8364117 DOI: 10.1186/s40001-021-00567-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 06/29/2021] [Indexed: 11/24/2022] Open
Abstract
Background To investigate the value of Dickkopf-related protein 3 (DKK3) on aerobic glycolysis in pancreatic cancer cells, where DKK3-overexpression is used to determine its effects on CD4+ T cells. Methods The BxPC-3-DKK3 cell line was constructed, and peripheral blood mononuclear cell (PBMC) was prepared. After isolated the CD4+ T cells, the lactic acid, glucose uptake ability, cellular viability, proliferation, apoptosis, and markers were detected by PCR and western blot, and the concentrations of multiple cytokines were determined using the ELISA method. Results After co-culture with pancreatic cancer cells overexpressing DKK3, the glucose uptake markedly, proliferation enhanced and apoptosis inhibited in CD4+ T cells. The co-culture model also revealed that DKK3-overexpression promotes the activation and regulates the metabolism and function of CD4+ T cells. Conclusions DKK3 alters the metabolic microenvironment of pancreatic cancer cells and further facilitates the function of CD4+ T cells which suggesting that DKK3 may have a therapeutic potential in pancreatic cancer.
Collapse
Affiliation(s)
- Qingqu Guo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Yiming Chu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China
| | - Hongbo Li
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Dike Shi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Lele Lin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Weifeng Lan
- Department of Surgery, Suichang County Hospital, No. 143 North Street, Suichang County, Lishui City, 323300, Zhejiang, China.
| | - Dan Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.
| |
Collapse
|
|
15
|
Jin P, Li J, Meng Y, Wu L, Bai M, Yu J, Meng X. PET/CT metabolic patterns in systemic immune activation: A new perspective on the assessment of immunotherapy response and efficacy. Cancer Lett 2021; 520:91-99. [PMID: 34237407 DOI: 10.1016/j.canlet.2021.06.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/24/2021] [Accepted: 06/29/2021] [Indexed: 02/07/2023]
Abstract
Despite advances in immunotherapy, extensive challenges remain in its clinical application. Positron emission tomography (PET)/computed tomography (CT) is widely used in the diagnosis and follow-up of malignant tumors and in the prediction of treatment outcomes. Successful cancer immunotherapy requires systemic immune activation. In addition to local immune responses, a systemic antitumor response involving primary and secondary lymphoid organs is required for tumor eradication. Immune-related adverse events (IRAEs) are considered to be a manifestation of excessive immune activation. PET/CT can monitor the metabolic changes in peripheral lymphoid organs and related organs. Thus, it can identify patients with effective immune activation and predict the efficacy and outcomes of immunotherapy. This review aimed to investigate the theoretical basis and feasibility of applying PET/CT for monitoring the immune activation status of peripheral lymphoid organs after immunotherapy and predict its effectiveness. Towards this goal, we reviewed the cellular components and structural composition of peripheral lymphoid organs, as well as their functions in the systemic immune response. We analyzed the theoretical basis and feasibility of applying PET/CT to monitor the immune activation status of peripheral lymphoid organs after immunotherapy to predict the effectiveness of immunotherapy.
Collapse
Affiliation(s)
- Peng Jin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jianing Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yingtao Meng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Leilei Wu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Department of Radiation Oncology, School of Medicine, Shandong University, Jinan, China
| | - Menglin Bai
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Department of Radiation Oncology, School of Medicine, Shandong University, Jinan, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| | - Xue Meng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| |
Collapse
|
|
16
|
Rodríguez-Rodríguez N, Madera-Salcedo IK, Cisneros-Segura JA, García-González HB, Apostolidis SA, Saint-Martin A, Esquivel-Velázquez M, Nguyen T, Romero-Rodríguez DP, Tsokos GC, Alcocer-Varela J, Rosetti F, Crispín JC. Protein phosphatase 2A B55β limits CD8+ T cell lifespan following cytokine withdrawal. J Clin Invest 2021; 130:5989-6004. [PMID: 32750040 DOI: 10.1172/jci129479] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 07/31/2020] [Indexed: 12/13/2022] Open
Abstract
How T cells integrate environmental cues into signals that limit the magnitude and length of immune responses is poorly understood. Here, we provide data that demonstrate that B55β, a regulatory subunit of protein phosphatase 2A, represents a molecular link between cytokine concentration and apoptosis in activated CD8+ T cells. Through the modulation of AKT, B55β induced the expression of the proapoptotic molecule Hrk in response to cytokine withdrawal. Accordingly, B55β and Hrk were both required for in vivo and in vitro contraction of activated CD8+ lymphocytes. We show that this process plays a role during clonal contraction, establishment of immune memory, and preservation of peripheral tolerance. This regulatory pathway may represent an unexplored opportunity to end unwanted immune responses or to promote immune memory.
Collapse
Affiliation(s)
- Noé Rodríguez-Rodríguez
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.,Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.,Division of Rheumatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Iris K Madera-Salcedo
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - J Alejandro Cisneros-Segura
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - H Benjamín García-González
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Sokratis A Apostolidis
- Division of Rheumatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Abril Saint-Martin
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Marcela Esquivel-Velázquez
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Tran Nguyen
- Division of Rheumatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Dámaris P Romero-Rodríguez
- Flow Cytometry Core Facility, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", Mexico City, Mexico
| | - George C Tsokos
- Division of Rheumatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jorge Alcocer-Varela
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Florencia Rosetti
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - José C Crispín
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.,Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| |
Collapse
|
|
17
|
Deleonardis A, Papale M. Methods to Study Posttranslational Modification Patterns in Cytotoxic T-Cells and Cancer. Methods Mol Biol 2021; 2325:137-153. [PMID: 34053056 DOI: 10.1007/978-1-0716-1507-2_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Protein posttranslational modifications (PTMs) regulate intracellular signaling associated with development and progression of many diseases; thus, they are key to understanding pathological mechanisms and set up more tailored therapies. In addition, many posttranslationally modified proteins are released into biological fluids and can be used as new and more specific biomarkers. Based on this evidence, we analyzed the role of some PTMs in cancer and described the correlation between specific PTMs and T-cells activation/inhibition in cancer microenvironment. In the second part of this chapter, we analyzed the most commonly used approaches for qualitative and quantitative determination of PTMs. The comparison of three distinct but often complementary methodologies such as immunoblotting, mass spectrometry, and ELISA assays has allowed to highlight the pros and cons of each approach with a focus on their current application and their future developments to obtain more confident biomarkers and therapeutic targets useful for diagnosis, prognosis, and monitoring of the response to therapy.
Collapse
Affiliation(s)
- Annamaria Deleonardis
- R&D Unit, Fluidia srl, Foggia, Italy
- Section of Nephrology, Dialysis and Transplantation, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Bari, Italy
| | - Massimo Papale
- Clinical Pathology Unit, Department of Laboratory Diagnostics, Policlinic University Hospital "Riuniti", Foggia, Italy.
| |
Collapse
|
|
18
|
Gary JM, Simmons JK, Xu J, Zhang S, Peat TJ, Watson N, Gamache BJ, Zhang K, Kovalchuk AL, Michalowski AM, Chen JQ, Thaiwong T, Kiupel M, Gaikwad S, Etienne M, Simpson RM, Dubois W, Testa JR, Mock BA. Hypomorphic mTOR Downregulates CDK6 and Delays Thymic Pre-T LBL Tumorigenesis. Mol Cancer Ther 2020; 19:2221-2232. [PMID: 32747423 DOI: 10.1158/1535-7163.mct-19-0671] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 01/14/2020] [Accepted: 07/13/2020] [Indexed: 11/16/2022]
Abstract
PI3K/AKT/mTOR pathway hyperactivation is frequent in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). To model inhibition of mTOR, pre-T-cell lymphoblastic leukemia/lymphoma (pre-T LBL) tumor development was monitored in mice with T lymphocyte-specific, constitutively active AKT (Lck-MyrAkt2) that were either crossed to mTOR knockdown (KD) mice or treated with the mTOR inhibitor everolimus. Lck-MyrAkt2;mTOR KD mice lived significantly longer than Lck-MyrAkt2;mTOR wild-type (WT) mice, although both groups ultimately developed thymic pre-T LBL. An increase in survival was also observed when Lck-MyrAkt2;mTOR WT mice were treated for 8 weeks with everolimus. The transcriptional profiles of WT and KD thymic lymphomas were compared, and Ingenuity Pathway Upstream Regulator Analysis of differentially expressed genes in tumors from mTOR WT versus KD mice identified let-7 and miR-21 as potential regulatory genes. mTOR KD mice had higher levels of let-7a and miR-21 than mTOR WT mice, and rapamycin induced their expression in mTOR WT cells. CDK6 was one of the most downregulated targets of both let-7 and miR21 in mTOR KD tumors. CDK6 overexpression and decreased expression of let-7 in mTOR KD cells rescued a G1 arrest phenotype. Combined mTOR (rapamycin) and CDK4/6 (palbociclib) inhibition decreased tumor size and proliferation in tumor flank transplants, increased survival in an intravenous transplant model of disseminated leukemia compared with single agent treatment, and cooperatively decreased cell viability in human T-ALL/LBL cell lines. Thus, mTOR KD mice provide a model to explore drug combinations synergizing with mTOR inhibitors and can be used to identify downstream targets of inhibition.
Collapse
Affiliation(s)
- Joy M Gary
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.,Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
| | - John K Simmons
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - Jinfei Xu
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Shuling Zhang
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - Tyler J Peat
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - Nicholas Watson
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - Benjamin J Gamache
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.,American University, Washington, DC
| | - Ke Zhang
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | | | | | - Jin-Qiu Chen
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - Tuddow Thaiwong
- Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
| | - Matti Kiupel
- Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
| | - Snehal Gaikwad
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - Maudeline Etienne
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - R Mark Simpson
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - Wendy Dubois
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland
| | - Joseph R Testa
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
| | - Beverly A Mock
- Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
| |
Collapse
|
|
19
|
Borne AL, Huang T, McCloud RL, Pachaiyappan B, Bullock TNJ, Hsu KL. Deciphering T Cell Immunometabolism with Activity-Based Protein Profiling. Curr Top Microbiol Immunol 2019; 420:175-210. [PMID: 30128827 PMCID: PMC7134364 DOI: 10.1007/82_2018_124] [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] [Indexed: 04/05/2023]
Abstract
As a major sentinel of adaptive immunity, T cells seek and destroy diseased cells using antigen recognition to achieve molecular specificity. Strategies to block checkpoint inhibition of T cell activity and thus reawaken the patient's antitumor immune responses are rapidly becoming standard of care for treatment of diverse cancers. Adoptive transfer of patient T cells genetically engineered with tumor-targeting capabilities is redefining the field of personalized medicines. The diverse opportunities for exploiting T cell biology in the clinic have prompted new efforts to expand the scope of targets amenable to immuno-oncology. Given the complex spatiotemporal regulation of T cell function and fate, new technologies capable of global molecular profiling in vivo are needed to guide selection of appropriate T cell targets and subsets. In this chapter, we describe the use of activity-based protein profiling (ABPP) to illuminate different aspects of T cell metabolism and signaling as fertile starting points for investigation. We highlight the merits of ABPP methods to enable target, inhibitor, and biochemical pathway discovery of T cells in the burgeoning field of immuno-oncology.
Collapse
Affiliation(s)
- Adam L Borne
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Tao Huang
- Department of Chemistry, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville, VA, 22904, USA
| | - Rebecca L McCloud
- Department of Chemistry, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville, VA, 22904, USA
| | - Boobalan Pachaiyappan
- Department of Chemistry, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville, VA, 22904, USA
| | - Timothy N J Bullock
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Ku-Lung Hsu
- Department of Chemistry, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville, VA, 22904, USA.
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
| |
Collapse
|
|
20
|
Clerc I, Moussa DA, Vahlas Z, Tardito S, Oburoglu L, Hope TJ, Sitbon M, Dardalhon V, Mongellaz C, Taylor N. Entry of glucose- and glutamine-derived carbons into the citric acid cycle supports early steps of HIV-1 infection in CD4 T cells. Nat Metab 2019; 1:717-730. [PMID: 32373781 PMCID: PMC7199465 DOI: 10.1038/s42255-019-0084-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 06/07/2019] [Indexed: 12/18/2022]
Abstract
The susceptibility of CD4 T cells to human immunodeficiency virus 1 (HIV-1) infection is regulated by glucose and glutamine metabolism, but the relative contributions of these nutrients to infection are not known. Here we show that glutaminolysis is the major pathway fuelling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in T-cell receptor-stimulated naïve, as well as memory CD4, subsets and is required for optimal HIV-1 infection. Under conditions of attenuated glutaminolysis, the α-ketoglutarate (α-KG) TCA rescues early steps in infection; exogenous α-KG promotes HIV-1 reverse transcription, rendering both naïve and memory cells more sensitive to infection. Blocking the glycolytic flux of pyruvate to lactate results in altered glucose carbon allocation to TCA and pentose phosphate pathway intermediates, an increase in OXPHOS and augmented HIV-1 reverse transcription. Moreover, HIV-1 infection is significantly higher in CD4 T cells selected on the basis of high mitochondrial biomass and OXPHOS activity. Therefore, the OXPHOS/aerobic glycolysis balance is a major regulator of HIV-1 infection in CD4 T lymphocytes.
Collapse
Affiliation(s)
- Isabelle Clerc
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Daouda Abba Moussa
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Zoi Vahlas
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Saverio Tardito
- Cancer Research UK, Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Leal Oburoglu
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Thomas J. Hope
- Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Marc Sitbon
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Valérie Dardalhon
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Cédric Mongellaz
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Naomi Taylor
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
- Present address: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
21
|
Menk AV, Scharping NE, Moreci RS, Zeng X, Guy C, Salvatore S, Bae H, Xie J, Young HA, Wendell SG, Delgoffe GM. Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions. Cell Rep 2019; 22:1509-1521. [PMID: 29425506 PMCID: PMC5973810 DOI: 10.1016/j.celrep.2018.01.040] [Citation(s) in RCA: 341] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Revised: 10/26/2017] [Accepted: 01/12/2018] [Indexed: 12/17/2022] Open
Abstract
To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes. Rather, TCR signaling promotes activation of pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import of pyruvate and facilitating breakdown into lactate. Inhibition of PDHK1 reveals this switch is required acutely for cytokine synthesis but dispensable for cytotoxicity. Functionally, cytokine synthesis is modulated via lactate dehydrogenase, which represses cytokine mRNA translation when aerobic glycolysis is disengaged. Our data provide mechanistic insight to metabolic contribution to effector T cell function and suggest that T cell function may be finely tuned through modulation of glycolytic activity.
Collapse
Affiliation(s)
- Ashley V Menk
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
| | - Nicole E Scharping
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Rebecca S Moreci
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
| | - Xue Zeng
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Tsinghua Medical University, Beijing, China
| | - Cliff Guy
- St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Sonia Salvatore
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Heekyong Bae
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21701, USA
| | - Jianxin Xie
- Cell Signaling Technology, Inc., Danvers, MA 01923, USA
| | - Howard A Young
- Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21701, USA
| | | | - Greg M Delgoffe
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| |
Collapse
|
|
22
|
Chen J, Hu L, Wang J, Cao Y, Zhu D, Chen L, Duan Y. Toxoplasma gondii excreted-secreted antigens suppress Foxp3 via PI3K-AKT-mTOR signaling pathway. J Cell Biochem 2019; 120:16044-16051. [PMID: 31074049 DOI: 10.1002/jcb.28884] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/15/2019] [Accepted: 02/28/2019] [Indexed: 01/07/2023]
Abstract
Toxoplasma gondii excreted-secreted antigens (ESA) cause spontaneous abortion or fetal teratogenesis during the pregnancy in mice, especially in the early stage. Those adverse pregnancy outcomes are due to the deficit in regulatory T cells (Tregs). Forkhead box P3 (Foxp3), a critical transcription factor, modulates Tregs differentiation and its function. Besides, phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling network is implicated in interfering with Foxp3 induction. We previously demonstrated that ESA diminished the number of Tregs and inhibited its function. And ESA suppressed Foxp3 expression via the attenuation of transforming growth factor β RII/Smad2/Smad3/Smad4 pathway. The current study aimed to investigate whether the PI3K-AKT-mTOR signaling network is involved in Foxp3 downregulation induced by ESA. We found that ESA upregulated PI3K, P-AKT, mTOR, and P-mTOR. Knockdown of PI3K cooperated with ESA to restore Foxp3 expression mediated by ESA. This suppressive role of ESA on Foxp3 expression was abrogated by AKT inhibitor. In addition, neutralization of Toll-like receptor 4 could restore the expression of Foxp3, PI3K, and its downstream effectors induced by ESA. Collectively, the findings indicated that ESA inhibited Foxp3 expression via the upregulation of PI3K-AKT-mTOR signaling pathway.
Collapse
Affiliation(s)
- Jinling Chen
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Liang Hu
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Jingjing Wang
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Yangqing Cao
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Dandan Zhu
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Liuting Chen
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Yinong Duan
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, People's Republic of China
| |
Collapse
|
|
23
|
Guo C, Chen S, Liu W, Ma Y, Li J, Fisher PB, Fang X, Wang XY. Immunometabolism: A new target for improving cancer immunotherapy. Adv Cancer Res 2019; 143:195-253. [PMID: 31202359 DOI: 10.1016/bs.acr.2019.03.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox regulation. While dysregulated metabolism (e.g., aerobic glycolysis also known as the Warburg effect) has long been recognized as a hallmark of cancer, recent discoveries of metabolic reprogramming in immune cells during their activation and differentiation have led to an emerging concept of "immunometabolism." Considering the recent success of cancer immunotherapy in the treatment of several cancer types, increasing research efforts are being made to elucidate alterations in metabolic profiles of cancer and immune cells during their interplays in the setting of cancer progression and immunotherapy. In this review, we summarize recent advances in studies of metabolic reprogramming in cancer as well as differentiation and functionality of various immune cells. In particular, we will elaborate how distinct metabolic pathways in the tumor microenvironment cause functional impairment of immune cells and contribute to immune evasion by cancer. Lastly, we highlight the potential of metabolically reprogramming the tumor microenvironment to promote effective and long-lasting antitumor immunity for improved immunotherapeutic outcomes.
Collapse
Affiliation(s)
- Chunqing Guo
- Department of Human & Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Shixian Chen
- Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Wenjie Liu
- Department of Human & Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Yibao Ma
- Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Juan Li
- Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Paul B Fisher
- Department of Human & Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Xianjun Fang
- Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Xiang-Yang Wang
- Department of Human & Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
| |
Collapse
|
|
24
|
Zhang B, Dai Q, Jin X, Liang D, Li X, Lu H, Liu Y, Ding J, Gao Q, Wen Y. Phosphoinositide 3-kinase/protein kinase B inhibition restores regulatory T cell's function in pulmonary sarcoidosis. J Cell Physiol 2019; 234:19911-19920. [PMID: 30945303 DOI: 10.1002/jcp.28589] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 03/04/2019] [Accepted: 03/06/2019] [Indexed: 12/28/2022]
Abstract
Sarcoidosis is a systemic granulomatous disease associated with Th1/ regulatory T cells (Treg) paradigm. PI3K/Akt signaling, critical for maintaining Treg's homeostasis, is aberrantly activated in sarcoidosis patients. Here we tested the role of the PI3K inhibitors, LY294002 and BKM120, in immune modulation in experimental pulmonary sarcoidosis, concerning Th1/Th17/Treg immune profile detected by fluorescence-activated cell sorting analysis or quantitative polymerase chain reaction, as well as the effect on Treg's suppressive functions. Our investigation showed abnormal activation of PI3K/Akt signaling both in lung and Treg in pulmonary sarcoidosis, along with decreased frequency and damaged function of Treg. Blockage of PI3K suppressed this signaling in Treg, rebalanced Th1/Treg, inhibited the production of inflammatory cytokines, and enhanced Treg's function. These results demonstrate the key role of the PI3K/Akt signaling in regulating Th1/Th2 rebalances and indicates that PI3K/Akt signaling is critical for the optimal Treg responses in pulmonary sarcoidosis. Thus, PI3K inhibitors have potential for therapeutic translation, and can be candidate for add-on drugs to treat pulmonary sarcoidosis.
Collapse
Affiliation(s)
- Bin Zhang
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Qianqian Dai
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Xuguang Jin
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Dongmei Liang
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Xiaojie Li
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Haiyan Lu
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Yu Liu
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Jingjing Ding
- Department of Respiratory Medicine, Jiangsu Key Laboratory of Molecular Medicine, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qian Gao
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| | - Yanting Wen
- Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China
| |
Collapse
|
|
25
|
Callender LA, Carroll EC, Bober EA, Henson SM. Divergent mechanisms of metabolic dysfunction drive fibroblast and T-cell senescence. Ageing Res Rev 2018; 47:24-30. [PMID: 29902528 DOI: 10.1016/j.arr.2018.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 05/22/2018] [Accepted: 06/05/2018] [Indexed: 12/15/2022]
Abstract
The impact of cellular senescence during ageing is well established, however senescence is now recognised to play a role in a variety of age related and metabolic diseases, such as cancer, autoimmune and cardiovascular diseases. It is therefore crucial to gain a better understanding of the mechanisms that control cellular senescence. In recent years our understanding of the intimate relationship between cell metabolism, cell signalling and cellular senescence has greatly improved. In this review we discuss the differing roles of glucose and protein metabolism in both senescent fibroblast and CD8+ T-cells, and explore the impact cellular metabolism has on the senescence-associated secretory phenotype (SASP) of these cell types.
Collapse
|
|
26
|
Arojo OA, Ouyang X, Liu D, Meng T, Kaech SM, Pereira JP, Su B. Active mTORC2 Signaling in Naive T Cells Suppresses Bone Marrow Homing by Inhibiting CXCR4 Expression. THE JOURNAL OF IMMUNOLOGY 2018; 201:908-915. [DOI: 10.4049/jimmunol.1800529] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 05/25/2018] [Indexed: 01/03/2023]
|
|
27
|
PKM2-dependent metabolic reprogramming in CD4 + T cells is crucial for hyperhomocysteinemia-accelerated atherosclerosis. J Mol Med (Berl) 2018; 96:585-600. [PMID: 29732501 DOI: 10.1007/s00109-018-1645-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 04/10/2018] [Accepted: 04/29/2018] [Indexed: 12/17/2022]
Abstract
Inflammation mediated by activated T cells plays an important role in the initiation and progression of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in ApoE-/- mice. Homocysteine (Hcy) activates T cells to secrete proinflammatory cytokines, especially interferon (IFN)-γ; however, the precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell inflammatory activation and effector functions. Our previous study demonstrated that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic reticulum (ER)-mitochondria coupling. In this study, we further explored the important role of glycolysis-mediated metabolic reprogramming in Hcy-activated CD4+ T cells. Mechanistically, Hcy-activated CD4+ T cell increased the protein expression and activity of pyruvate kinase muscle isozyme 2 (PKM2), the final rate-limiting enzyme in glycolysis, via the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin signaling pathway. Knockdown of PKM2 by small interfering RNA reduced Hcy-induced CD4+ T cell IFN-γ secretion. Furthermore, we generated T cell-specific PKM2 knockout mice by crossing LckCre transgenic mice with PKM2fl/fl mice and observed that Hcy-induced glycolysis and oxidative phosphorylation were both diminished in PKM2-deficient CD4+ T cells with reduced glucose and lipid metabolites, and subsequently reduced IFN-γ secretion. T cell-depleted apolipoprotein E-deficient (ApoE-/-) mice adoptively transferred with PKM2-deficient CD4+ T cells, compared to mice transferred with control cells, showed significantly decreased HHcy-accelerated early atherosclerotic lesion formation. In conclusion, this work indicates that the PKM2-dependent glycolytic-lipogenic axis, a novel mechanism of metabolic regulation, is crucial for HHcy-induced CD4+ T cell activation to accelerate early atherosclerosis in ApoE-/- mice. KEY MESSAGES Metabolic reprogramming is crucial for Hcy-induced CD4+ T cell inflammatory activation. Hcy activates the glycolytic-lipogenic pathway in CD4+ T cells via PKM2. Targeting PKM2 attenuated HHcy-accelerated early atherosclerosis in ApoE-/- mice in vivo.
Collapse
|
|
28
|
Li XY, Su L, Jiang YM, Gao WB, Xu CW, Zeng CQ, Song J, Xu Y, Weng WC, Liang WB. The Antitumor Effect of Xihuang Pill on Treg Cells Decreased in Tumor Microenvironment of 4T1 Breast Tumor-Bearing Mice by PI3K/AKT~AP-1 Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:6714829. [PMID: 29849718 PMCID: PMC5937580 DOI: 10.1155/2018/6714829] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/19/2018] [Accepted: 03/07/2018] [Indexed: 12/20/2022]
Abstract
To study the antitumor effect of Xihuang pill (XHP) on the number of Treg cells in the tumor microenvironment of 4T1 breast tumor-bearing mice by PI3K/AKT/AP-1 pathway, a mouse model was established. Flow cytometry (FCM) and immunohistochemistry (IHC) were used to detect the number of Treg cells in the tumor microenvironment; terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to detect the apoptosis of Treg cells in tumor microenvironment. Quantitative real-time PCR (RT-qPCR) was used to detect the mRNA expression of PI3K, AKT, and AP-1 in Treg cells in tumor microenvironment; immunofluorescence (IF) and Western Blot (WB) were used to detect the protein expression of PI3K, AKT, and AP-1 in Treg cells in tumor microenvironment. Compared with the naive control group, the tumor weight in XHP groups decreased significantly (P < 0.05); FCM and IHC results showed that the number of Treg cells in the tumor microenvironment decreased with the dose of XHP groups (P < 0.05); TUNEL staining showed that the number of Treg cells in tumor microenvironment increased with the dose of XHP groups (P < 0.05); RT-qPCR results showed that the mRNA expression of PI3K and AKT in Treg cells decreased with the dose of XHP groups, while RNA expression of AP-1 increased with the dose of XHP groups (P < 0.05); IF and WB results showed that the protein expression of PI3K and AKT in Treg cells decreased with the dose of XHP groups and the protein expression of AP-1 increased with the dose of XHP groups (P < 0.05). The results suggested that XHP decreased the number of Treg cells via inhibiting PI3K and AKT expression and upregulating AP-1 expression in Treg cells and then promoting the apoptosis of Treg cells. Thus, XHP could improve the immunosuppressive state of tumor microenvironment and reverse the immune escape to inhibit tumor growth.
Collapse
Affiliation(s)
- Xin-ye Li
- Medical College of Dalian University, Dalian 116622, China
| | - Liang Su
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Yi-ming Jiang
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Wen-bin Gao
- Department of Medical Oncology, The 3rd Affiliated Hospital of Shenzhen University, Shenzhen 518001, China
| | - Chun-wei Xu
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | | | - Jie Song
- Medical College of Dalian University, Dalian 116622, China
| | - Yu Xu
- Medical College of Dalian University, Dalian 116622, China
| | - Wen-cai Weng
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Wen-bo Liang
- Medical College of Dalian University, Dalian 116622, China
| |
Collapse
|
|
29
|
Feist M, Schwarzfischer P, Heinrich P, Sun X, Kemper J, von Bonin F, Perez-Rubio P, Taruttis F, Rehberg T, Dettmer K, Gronwald W, Reinders J, Engelmann JC, Dudek J, Klapper W, Trümper L, Spang R, Oefner PJ, Kube D. Cooperative STAT/NF-κB signaling regulates lymphoma metabolic reprogramming and aberrant GOT2 expression. Nat Commun 2018; 9:1514. [PMID: 29666362 PMCID: PMC5904148 DOI: 10.1038/s41467-018-03803-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 03/14/2018] [Indexed: 12/14/2022] Open
Abstract
Knowledge of stromal factors that have a role in the transcriptional regulation of metabolic pathways aside from c-Myc is fundamental to improvements in lymphoma therapy. Using a MYC-inducible human B-cell line, we observed the cooperative activation of STAT3 and NF-κB by IL10 and CpG stimulation. We show that IL10 + CpG-mediated cell proliferation of MYClow cells depends on glutaminolysis. By 13C- and 15N-tracing of glutamine metabolism and metabolite rescue experiments, we demonstrate that GOT2 provides aspartate and nucleotides to cells with activated or aberrant Jak/STAT and NF-κB signaling. A model of GOT2 transcriptional regulation is proposed, in which the cooperative phosphorylation of STAT3 and direct joint binding of STAT3 and p65/NF-κB to the proximal GOT2 promoter are important. Furthermore, high aberrant GOT2 expression is prognostic in diffuse large B-cell lymphoma underscoring the current findings and importance of stromal factors in lymphoma biology. Metabolic rewiring of cancer cells can be driven by both extrinsic and intrinsic factors. Here the authors show that microenvironmental factors induce metabolic rewiring of B-cell lymphoma through activation of STAT3 and NF-ΚB resulting in upregulation of the aminotransferase GOT2 and glutamine addiction.
Collapse
Affiliation(s)
- Maren Feist
- Clinic of Haematology and Medical Oncology, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany.,Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany
| | - Philipp Schwarzfischer
- Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.,Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany
| | - Paul Heinrich
- Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany.,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany
| | - Xueni Sun
- Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany.,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany
| | - Judith Kemper
- Clinic of Haematology and Medical Oncology, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany
| | - Frederike von Bonin
- Clinic of Haematology and Medical Oncology, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany
| | - Paula Perez-Rubio
- Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany.,Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany
| | - Franziska Taruttis
- Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.,Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany
| | - Thorsten Rehberg
- Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany
| | - Katja Dettmer
- Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany.,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany
| | - Wolfram Gronwald
- Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.,Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany.,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany
| | - Jörg Reinders
- Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany
| | - Julia C Engelmann
- Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany.,Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany.,NIOZ Royal Netherlands Institute for Sea Research and Utrecht University, 1790 AB, Den Burg, The Netherlands
| | - Jan Dudek
- Institute of Biochemistry, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany
| | - Wolfram Klapper
- Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany.,Department of Pathology, Hematopathology Section, UKSH Campus Kiel, 24105, Kiel, Germany
| | - Lorenz Trümper
- Clinic of Haematology and Medical Oncology, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany.,Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany
| | - Rainer Spang
- Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany.,Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany
| | - Peter J Oefner
- Institute of Functional Genomics, University of Regensburg, Bavaria, 93053, Regensburg, Germany
| | - Dieter Kube
- Clinic of Haematology and Medical Oncology, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany. .,Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany. .,Network BMBF eMed MMML-Demonstrators, 37099 Göttingen / 93053 Regensburg, Germany.
| |
Collapse
|
|
30
|
Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, Watkins SC, Delgoffe GM. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med 2018; 215:1091-1100. [PMID: 29511066 PMCID: PMC5881463 DOI: 10.1084/jem.20171068] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 12/18/2017] [Accepted: 02/08/2018] [Indexed: 12/22/2022] Open
Abstract
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function. We hypothesized that 4-1BB signaling might provide metabolic support to tumor-infiltrating T cells. 4-1BB costimulation of CD8+ T cells results in enhanced mitochondrial capacity (suggestive of fusion) and engages PGC1α-mediated pathways via activation of p38-MAPK. 4-1BB treatment of mice improves metabolic sufficiency in endogenous and adoptive therapeutic CD8+ T cells. 4-1BB stimulation combined with PD-1 blockade results in robust antitumor immunity. Sequenced studies revealed the metabolic support afforded by 4-1BB agonism need not be continuous and that a short course of anti-4-1BB pretreatment was sufficient to provide a synergistic response. Our studies highlight metabolic reprogramming as the dominant effect of 4-1BB therapy and suggest that combinatorial strategies using 4-1BB agonism may help overcome the immunosuppressive metabolic landscape of the tumor microenvironment.
Collapse
Affiliation(s)
- Ashley V Menk
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
| | - Nicole E Scharping
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA
| | - Dayana B Rivadeneira
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA
| | | | - McLane J Watson
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA
| | - Deanna Dunstane
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
| | - Simon C Watkins
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA.,Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA
| | - Greg M Delgoffe
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA .,Department of Immunology, University of Pittsburgh, Pittsburgh, PA
| |
Collapse
|
|
31
|
Machacek M, Slawson C, Fields PE. O-GlcNAc: a novel regulator of immunometabolism. J Bioenerg Biomembr 2018; 50:223-229. [PMID: 29404877 DOI: 10.1007/s10863-018-9744-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 01/18/2018] [Indexed: 12/26/2022]
Abstract
The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4+ T cells are essential for the adaptive immune response leading to the eradication of specific pathogens. However, when T cells are inappropriately over-active, they can drive autoimmunity, allergic disease, and chronic inflammation. The mechanisms by which metabolic changes influence function in CD4+ T cells are not fully understood. The post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine), dynamically cycles on and off of intracellular proteins as cells respond to their environment and flux through metabolic pathways changes. As the rate of O-GlcNAc cycling fluctuates, protein function, stability, and/or localization can be affected. Thus, O-GlcNAc is critically poised at the nexus of cellular metabolism and function. This review highlights the intra- and extracellular metabolic factors that influence CD4+ T cell activation and differentiation and how O-GlcNAc regulates these processes. We also propose areas of future research that may illuminate O-GlcNAc's role in the plasticity and pathogenicity of CD4+ T cells and uncover new potential therapeutic targets.
Collapse
Affiliation(s)
- Miranda Machacek
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA
| | - Chad Slawson
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA
| | - Patrick E Fields
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA.
| |
Collapse
|
|
32
|
Tran CW, Saibil SD, Le Bihan T, Hamilton SR, Lang KS, You H, Lin AE, Garza KM, Elford AR, Tai K, Parsons ME, Wigmore K, Vainberg MG, Penninger JM, Woodgett JR, Mak TW, Ohashi PS. Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation. THE JOURNAL OF IMMUNOLOGY 2017; 199:4056-4065. [DOI: 10.4049/jimmunol.1600396] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 10/05/2017] [Indexed: 11/19/2022]
|
|
33
|
The CSF Immune Response in HIV-1-Associated Cryptococcal Meningitis: Macrophage Activation, Correlates of Disease Severity, and Effect of Antiretroviral Therapy. J Acquir Immune Defic Syndr 2017; 75:299-307. [PMID: 28346317 PMCID: PMC5469563 DOI: 10.1097/qai.0000000000001382] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Supplemental Digital Content is Available in the Text. Background: Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART). Methodology: We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks). Findings: CSF was available from 57 persons (median CD4 34/μL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14+ and 35% CD14− monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4+, CD8+, and CD4−CD8− T cells and lower interleukin-6, G-CSF, and interleukin-5 concentrations. High intracranial pressure (≥30 cm H2O) was associated with fewer T cells, a higher fungal burden, and larger Cryptococcus organisms. Mortality was associated with reduced interferon-gamma concentrations and CD4−CD8− T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206. Conclusions: Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV-associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease.
Collapse
|
|
34
|
Andrejeva G, Rathmell JC. Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors. Cell Metab 2017; 26:49-70. [PMID: 28683294 PMCID: PMC5555084 DOI: 10.1016/j.cmet.2017.06.004] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 05/22/2017] [Accepted: 06/09/2017] [Indexed: 12/20/2022]
Abstract
It has been appreciated for nearly 100 years that cancer cells are metabolically distinct from resting tissues. More recently understood is that this metabolic phenotype is not unique to cancer cells but instead reflects characteristics of proliferating cells. Similar metabolic transitions also occur in the immune system as cells transition from resting state to stimulated effectors. A key finding in immune metabolism is that the metabolic programs of different cell subsets are distinctly associated with immunological function. Further, interruption of those metabolic pathways can shift immune cell fate to modulate immunity. These studies have identified numerous metabolic similarities between cancer and immune cells but also critical differences that may be exploited and that affect treatment of cancer and immunological diseases.
Collapse
Affiliation(s)
- Gabriela Andrejeva
- Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center and Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Jeffrey C Rathmell
- Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center and Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
| |
Collapse
|
|
35
|
Patsoukis N, Weaver JD, Strauss L, Herbel C, Seth P, Boussiotis VA. Immunometabolic Regulations Mediated by Coinhibitory Receptors and Their Impact on T Cell Immune Responses. Front Immunol 2017; 8:330. [PMID: 28443090 PMCID: PMC5387055 DOI: 10.3389/fimmu.2017.00330] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 03/08/2017] [Indexed: 12/18/2022] Open
Abstract
Host immunity provides wide spectrum protection that serves to eradicate pathogens and cancer cells, while maintaining self-tolerance and immunological homeostasis. Ligation of the T cell receptor (TCR) by antigen activates signaling pathways that coordinately induce aerobic glycolysis, mitochondrial activity, anabolic metabolism, and T effector cell differentiation. Activation of PI3K, Akt, and mTOR triggers the switch to anabolic metabolism by inducing transcription factors such as Myc and HIF1, and the glucose transporter Glut1, which is pivotal for the increase of glucose uptake after T cell activation. Activation of MAPK signaling is required for glucose and glutamine utilization, whereas activation of AMPK is critical for energy balance and metabolic fitness of T effector and memory cells. Coinhibitory receptors target TCR-proximal signaling and generation of second messengers. Imbalanced activation of such signaling pathways leads to diminished rates of aerobic glycolysis and impaired mitochondrial function resulting in defective anabolic metabolism and altered T cell differentiation. The coinhibitory receptors mediate distinct and synergistic effects on the activation of signaling pathways thereby modifying metabolic programs of activated T cells and resulting in altered immune functions. Understanding and therapeutic targeting of metabolic programs impacted by coinhibitory receptors might have significant clinical implications for the treatment of chronic infections, cancer, and autoimmune diseases.
Collapse
Affiliation(s)
- Nikolaos Patsoukis
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA, USA.,Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jessica D Weaver
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA, USA.,Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Laura Strauss
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA, USA.,Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christoph Herbel
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA, USA.,Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Pankaj Seth
- Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.,Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Vassiliki A Boussiotis
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA, USA.,Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.,Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
36
|
Depurinized milk downregulates rat thymus MyD88/Akt/p38 function, NF-κB-mediated inflammation, caspase-1 activity but not the endonuclease pathway: in vitro/in vivo study. Sci Rep 2017; 7:41971. [PMID: 28176796 PMCID: PMC5296740 DOI: 10.1038/srep41971] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 01/04/2017] [Indexed: 12/17/2022] Open
Abstract
The aim of this study was the evaluation of 15 days dietary regimen of depurinized (DP) milk (obtained using our patented technological procedures) or 1.5% fat UHT milk instead of standard chow diet, on rat thymus and bone marrow MyD88/Akt/p38, NF-κB, caspase-1 and endonuclease pathways, in relation to peripheral blood cell composition. To determine whether the reduced mass of the thymus is a consequence of the direct effect of DP/UHT milk on apoptosis of thymocytes, in vitro Annexin-V-FITC/PI assay was performed. Significant decreases in the thymus wet weight, thymocyte MyD88, Akt-1/phospho-Akt-1 kinase, p38/phospho-p38, NF-κB, caspase-1 activity and CD4+/CD8+ antigen expression were obtained, especially in the DP milk group. The activity of thymocyte alkaline and acid DNase increased in the DP but not in the UHT milk group. The level of IL-6 significantly decreased in DP milk treated group, while the level of total TGF-β and IL-6 increased in UHT milk group. Significant differences in hematological parameters were obtained in commercial milk fed group. Observed results about prevention of experimental diabetes in DP pretreated groups may suggest that purine compounds, uric acid and other volatile toxic compounds of commercial milk may suppress oral tolerance, probably via IL-6 and TGF-β cytokine effects.
Collapse
|
|
37
|
Kwon BI, Kim TW, Shin K, Kim YH, Yuk CM, Yuk JM, Shin DM, Jo EK, Lee CH, Lee SH. Enhanced Th2 cell differentiation and function in the absence of Nox2. Allergy 2017; 72:252-265. [PMID: 27253713 DOI: 10.1111/all.12944] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2016] [Indexed: 01/05/2023]
Abstract
BACKGROUND Patients with chronic granulomatous disease (CGD), whom inherit abnormal function of NADPH oxidase 2 (Nox2), suffer from hyperinflammatory responses in lung as well as bacterial and fungal infection. There have been studies to reveal the function of Nox2 in hyperinflammatory diseases, especially in asthma, but the exact role of Nox2 in asthma is still unclear and controversial. Therefore, we attempted to clarify the exact role of Nox2 in asthma, using various experimental asthma models. METHODS Asthma phenotypes were analyzed in response to various allergen-induced experimental asthma using Nox2-deficient mice and recombinase gene-activating-1-deficient mice. To understand the underlying mechanisms of exaggerated Th2 effector functions, we investigated the degree of T-cell activation, levels of activation-induced cell death (AICD), and regulatory T (Treg)-cell differentiation in Nox2-deficient T cells. RESULTS Asthma phenotypes were increased through enhanced Th2 differentiation and function in Nox2-null mice regardless of dose and route of various allergens. Nox2-deficient T cells also showed hyperactivation, reduced AICD, and diminished Treg-cell differentiation through increased AKT phosphorylation (T308/S473) and enhanced mitochondrial ROS production. CONCLUSION Our findings indicate that Nox2 deficiency results in exaggerated experimental asthma, which is caused by enhanced Th2 effector function in a T-cell-intrinsic manner.
Collapse
Affiliation(s)
- B.-I. Kwon
- Graduate School of Medical Science and Engineering (GSMSE); Biomedical Research Center; KAIST Institute of the BioCentury; Korea Advanced Institute of Science and Technology (KAIST); Daejeon Korea
- K-herb Research Center; Korea Institute of Oriental Medicine; Daejeon Korea
| | - T. W. Kim
- Graduate School of Medical Science and Engineering (GSMSE); Biomedical Research Center; KAIST Institute of the BioCentury; Korea Advanced Institute of Science and Technology (KAIST); Daejeon Korea
| | - K. Shin
- Graduate School of Medical Science and Engineering (GSMSE); Biomedical Research Center; KAIST Institute of the BioCentury; Korea Advanced Institute of Science and Technology (KAIST); Daejeon Korea
- Department of Dermatology; School of Medicine; Pusan National University; Busan Korea
| | - Y. H. Kim
- Graduate School of Medical Science and Engineering (GSMSE); Biomedical Research Center; KAIST Institute of the BioCentury; Korea Advanced Institute of Science and Technology (KAIST); Daejeon Korea
- Korean Medicine Convergence Research Division; Korea Institute of Oriental Medicine; Daejeon Korea
| | - C. M. Yuk
- Graduate School of Medical Science and Engineering (GSMSE); Biomedical Research Center; KAIST Institute of the BioCentury; Korea Advanced Institute of Science and Technology (KAIST); Daejeon Korea
| | - J.-M. Yuk
- Department of Microbiology; Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon Korea
| | - D.-M. Shin
- Department of Microbiology; Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon Korea
| | - E.-K. Jo
- Department of Microbiology; Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon Korea
| | - C.-H. Lee
- Animal Model Center; Korea Research Institute of Bioscience and Biotechnology; Daejeon Korea
| | - S.-H. Lee
- Graduate School of Medical Science and Engineering (GSMSE); Biomedical Research Center; KAIST Institute of the BioCentury; Korea Advanced Institute of Science and Technology (KAIST); Daejeon Korea
| |
Collapse
|
|
38
|
Ding Y, Han R, Jiang W, Xiao J, Liu H, Chen X, Li X, Hao J. Programmed Death Ligand 1 Plays a Neuroprotective Role in Experimental Autoimmune Neuritis by Controlling Peripheral Nervous System Inflammation of Rats. THE JOURNAL OF IMMUNOLOGY 2016; 197:3831-3840. [PMID: 27798164 DOI: 10.4049/jimmunol.1601083] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 09/20/2016] [Indexed: 01/22/2023]
Abstract
Programmed death 1 (PD-1; CD279), a member of the CD28 family, is an inhibitory receptor on T cells and is responsible for T cell dysfunction in infectious diseases and cancers. The ligand for PD-1, programmed death ligand 1 (PD-L1; also known as B7-H1, CD274), is a member of the B7 family. The engagement of PD-1 with programmed death ligand can downregulate autoreactive T cells that participate in multiple autoimmune diseases. Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome, and the pathogenesis of EAN is mediated principally through T cells and macrophages. In this study, we investigated the effects of PD-L1 in EAN rats. For preventative and therapeutic management, we administered PD-L1, which successfully decreased the severity of EAN; it alleviated the neurologic course of EAN, as well as inhibited the infiltration of inflammatory cells and demyelination of sciatic nerves. Our data revealed that PD-L1 treatment inhibited lymphocyte proliferation and altered T cell differentiation by inducing decreases in IFN-γ+CD4+ Th1 cells and IL-17+CD4+ Th17 cells and increases in IL-4+CD4+ Th2 cells and Foxp3+CD4+ regulatory T cells. The expression levels of p-STAT3 and Foxp3 were significantly different in PD-L1-treated groups compared with the control group. Additionally, PD-L1 regulated the expression of Foxp3 and p-STAT3 in EAN, probably by inhibiting PI3K/AKT/mTOR signaling expression. In summary, PD-L1 is a potentially useful agent for the treatment of EAN because of its anti-inflammatory and neuroprotective effects.
Collapse
Affiliation(s)
- Yanan Ding
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Ranran Han
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Wei Jiang
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jinting Xiao
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Haijie Liu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xiuju Chen
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xiaowen Li
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Junwei Hao
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| |
Collapse
|
|
39
|
Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, Warmoes MO, de Cubas AA, MacIver NJ, Locasale JW, Turka LA, Wells AD, Rathmell JC. Foxp3 and Toll-like receptor signaling balance T reg cell anabolic metabolism for suppression. Nat Immunol 2016; 17:1459-1466. [PMID: 27695003 DOI: 10.1038/ni.3577] [Citation(s) in RCA: 412] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 09/02/2016] [Indexed: 02/07/2023]
Abstract
CD4+ effector T cells (Teff cells) and regulatory T cells (Treg cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K (phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for Teff cell proliferation and inflammatory function, the mechanisms that regulate Treg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote Treg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired Treg cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of Treg cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of Treg cells.
Collapse
Affiliation(s)
- Valerie A Gerriets
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
| | - Rigel J Kishton
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
| | - Marc O Johnson
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.,Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee, USA
| | - Sivan Cohen
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
| | - Peter J Siska
- Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee, USA
| | - Amanda G Nichols
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
| | - Marc O Warmoes
- Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Aguirre A de Cubas
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nancie J MacIver
- Division of Pediatric Endocrinology and Diabetes, Duke University, Durham, North Carolina, USA
| | - Jason W Locasale
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
| | - Laurence A Turka
- Massachusetts General Hospital, Center for Transplantation Sciences, Boston, Massachusetts, USA
| | - Andrew D Wells
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jeffrey C Rathmell
- Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee, USA
| |
Collapse
|
|
40
|
High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia. Blood 2016; 128:2229-2240. [PMID: 27670423 DOI: 10.1182/blood-2016-01-692855] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 09/08/2016] [Indexed: 12/20/2022] Open
Abstract
Activating NOTCH1 mutations are frequent in human T-cell acute lymphoblastic leukemia (T-ALL) and Notch inhibitors (γ-secretase inhibitors [GSIs]) have produced responses in patients with relapsed, refractory disease. However, sustained responses, although reported, are uncommon, suggesting that other pathways can substitute for Notch in T-ALL. To address this possibility, we first generated KrasG12D transgenic mice with T-cell-specific expression of the pan-Notch inhibitor, dominant-negative Mastermind (DNMAML). These mice developed leukemia, but instead of accessing alternative oncogenic pathways, the tumor cells acquired Notch1 mutations and subsequently deleted DNMAML, reinforcing the notion that activated Notch1 is particularly transforming within the context of T-cell progenitors. We next took a candidate approach to identify oncogenic pathways downstream of Notch, focusing on Myc and Akt, which are Notch targets in T-cell progenitors. KrasG12D mice transduced with Myc developed T-ALLs that were GSI-insensitive and lacked Notch1 mutations. In contrast, KrasG12D mice transduced with myristoylated AKT developed GSI-sensitive T-ALLs that acquired Notch1 mutations. Thus, Myc can substitute for Notch1 in leukemogenesis, whereas Akt cannot. These findings in primary tumors extend recent work using human T-ALL cell lines and xenografts and suggest that the Notch/Myc signaling axis is of predominant importance in understanding both the selective pressure for Notch mutations in T-ALL and response and resistance of T-ALL to Notch pathway inhibitors.
Collapse
|
|
41
|
Siska PJ, van der Windt GJW, Kishton RJ, Cohen S, Eisner W, MacIver NJ, Kater AP, Weinberg JB, Rathmell JC. Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia. THE JOURNAL OF IMMUNOLOGY 2016; 197:2532-40. [PMID: 27511728 DOI: 10.4049/jimmunol.1502464] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 07/15/2016] [Indexed: 12/14/2022]
Abstract
Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction.
Collapse
Affiliation(s)
- Peter J Siska
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232
| | | | - Rigel J Kishton
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710
| | - Sivan Cohen
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710
| | - William Eisner
- Department of Pediatrics, Duke University, Durham, NC 27710
| | | | - Arnon P Kater
- Department of Hematology, Academic Medical Center, 1100 DD Amsterdam, the Netherlands; Lymphoma and Myeloma Center Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - J Brice Weinberg
- Department of Medicine, Duke University, Durham, NC 27708; and Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC 27705
| | - Jeffrey C Rathmell
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232;
| |
Collapse
|
|
42
|
Gill KS, Fernandes P, O'Donovan TR, McKenna SL, Doddakula KK, Power DG, Soden DM, Forde PF. Glycolysis inhibition as a cancer treatment and its role in an anti-tumour immune response. Biochim Biophys Acta Rev Cancer 2016; 1866:87-105. [PMID: 27373814 DOI: 10.1016/j.bbcan.2016.06.005] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 06/29/2016] [Accepted: 06/30/2016] [Indexed: 12/23/2022]
Abstract
Increased glycolysis is the main source of energy supply in cancer cells that use this metabolic pathway for ATP generation. Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the "hallmarks of cancer". The immune system can prevent tumour growth by eliminating cancer cells but this editing process ultimately results in poorly immunogenic cells remaining allowing for unchallenged tumour growth. In this review we look at the glycolysis pathway as a target for cancer treatments. We also examine the interplay between the glycolysis modulation and the immune response as an anti-cancer therapy.
Collapse
Affiliation(s)
- Kheshwant S Gill
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland; Cardiothoracic Surgery Department, Cork University Hospital, Cork, Ireland
| | - Philana Fernandes
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland
| | - Tracey R O'Donovan
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland
| | - Sharon L McKenna
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland
| | | | - Derek G Power
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland; Department of Medical Oncology, Mercy University Hospital, Grenville Place, Cork, Ireland
| | - Declan M Soden
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland
| | - Patrick F Forde
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Cork, Ireland.
| |
Collapse
|
|
43
|
Cammann C, Rath A, Reichl U, Lingel H, Brunner-Weinzierl M, Simeoni L, Schraven B, Lindquist JA. Early changes in the metabolic profile of activated CD8(+) T cells. BMC Cell Biol 2016; 17:28. [PMID: 27387758 PMCID: PMC4937576 DOI: 10.1186/s12860-016-0104-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 06/17/2016] [Indexed: 01/11/2023] Open
Abstract
Background Antigenic stimulation of the T cell receptor (TCR) initiates a change from a resting state into an activated one, which ultimately results in proliferation and the acquisition of effector functions. To accomplish this task, T cells require dramatic changes in metabolism. Therefore, we investigated changes of metabolic intermediates indicating for crucial metabolic pathways reflecting the status of T cells. Moreover we analyzed possible regulatory molecules required for the initiation of the metabolic changes. Results We found that proliferation inducing conditions result in an increase in key glycolytic metabolites, whereas the citric acid cycle remains unaffected. The upregulation of glycolysis led to a strong lactate production, which depends upon AKT/PKB, but not mTOR. The observed upregulation of lactate dehydrogenase results in increased lactate production, which we found to be dependent on IL-2 and to be required for proliferation. Additionally we observed upregulation of Glucose-transporter 1 (GLUT1) and glucose uptake upon stimulation, which were surprisingly not influenced by AKT inhibition. Conclusions Our findings suggest that AKT plays a central role in upregulating glycolysis via induction of lactate dehydrogenase expression, but has no impact on glucose uptake of T cells. Furthermore, under apoptosis inducing conditions, T cells are not able to upregulate glycolysis and induce lactate production. In addition maintaining high glycolytic rates strongly depends on IL-2 production. Electronic supplementary material The online version of this article (doi:10.1186/s12860-016-0104-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Clemens Cammann
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, Germany.
| | - Alexander Rath
- Max-Planck-Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany
| | - Udo Reichl
- Max-Planck-Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany
| | - Holger Lingel
- Department of Experimental Pediatrics, Otto-von-Guericke-University, Magdeburg, Germany
| | | | - Luca Simeoni
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, Germany
| | - Burkhart Schraven
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, Germany.,Department of Immune Control, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Jonathan A Lindquist
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, Germany.,Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg, Germany
| |
Collapse
|
|
44
|
Kitz A, de Marcken M, Gautron AS, Mitrovic M, Hafler DA, Dominguez-Villar M. AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Rep 2016; 17:1169-83. [PMID: 27312110 DOI: 10.15252/embr.201541905] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 05/13/2016] [Indexed: 12/22/2022] Open
Abstract
Foxp3(+) regulatory T cells (Tregs) exhibit plasticity, which dictates their function. Secretion of the inflammatory cytokine IFNγ, together with the acquisition of a T helper 1 (Th1)-like effector phenotype as observed in cancer, infection, and autoimmune diseases, is associated with loss of Treg suppressor function through an unknown mechanism. Here, we describe the signaling events driving the generation of human Th1-Tregs. Using a genome-wide gene expression approach and pathway analysis, we identify the PI3K/AKT/Foxo1/3 signaling cascade as the major pathway involved in IFNγ secretion by human Tregs. Furthermore, we describe the opposing roles of AKT isoforms in Th1-Treg generation ex vivo Finally, we employ multiple sclerosis as an in vivo model with increased but functionally defective Th1-Tregs. We show that the PI3K/AKT/Foxo1/3 pathway is activated in ex vivo-isolated Tregs from untreated relapsing-remitting MS patients and that blockade of the pathway inhibits IFNγ secretion and restores the immune suppressive function of Tregs. These data define a fundamental pathway regulating the function of human Tregs and suggest a novel treatment paradigm for autoimmune diseases.
Collapse
Affiliation(s)
- Alexandra Kitz
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Marine de Marcken
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Anne-Sophie Gautron
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Mitja Mitrovic
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - David A Hafler
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | | |
Collapse
|
|
45
|
Delgoffe GM, Powell JD. Feeding an army: The metabolism of T cells in activation, anergy, and exhaustion. Mol Immunol 2016; 68:492-6. [PMID: 26256793 DOI: 10.1016/j.molimm.2015.07.026] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/10/2015] [Accepted: 07/21/2015] [Indexed: 12/23/2022]
Abstract
Through the direct control of infection or by providing cytokine signals to other cellular players, T cells play a central role in the orchestration of the immune response. However, in many disease states, T cells are rendered dysfunctional, unable to carry out their effector functions. As T cell activation is bioenergetically demanding, some T cell dysfunction can have metabolic underpinnings. In this review, we will discuss how T cells are programmed to fuel their effector response, and how programmed or pathologic changes can disrupt their ability to generate the energy needed to proliferate and carry out their critical functions.
Collapse
Affiliation(s)
- Greg M Delgoffe
- Tumor Microenvironment Center, Department of Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, United States.
| | - Jonathan D Powell
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21223, United States
| |
Collapse
|
|
46
|
Cell surface Glut1 levels distinguish human CD4 and CD8 T lymphocyte subsets with distinct effector functions. Sci Rep 2016; 6:24129. [PMID: 27067254 PMCID: PMC4828702 DOI: 10.1038/srep24129] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 03/15/2016] [Indexed: 02/07/2023] Open
Abstract
CD4 and CD8 T lymphocyte activation requires the generation of sufficient energy to support new biosynthetic demands. Following T cell receptor (TCR) engagement, these requirements are met by an increased glycolysis, due, at least in part, to induction of the Glut1 glucose transporter. As Glut1 is upregulated on tumor cells in response to hypoxia, we assessed whether surface Glut1 levels regulate the antigen responsiveness of human T lymphocytes in both hypoxic and atmospheric oxygen conditions. Notably, Glut1 upregulation in response to TCR stimulation was significantly higher in T lymphocytes activated under hypoxic as compared to atmospheric oxygen conditions. Furthermore, TCR-stimulated human T lymphocytes sorted on the basis of Glut1-Lo and Glut1-Hi profiles maintained distinct characteristics, irrespective of the oxygen tension. While T cells activated in hypoxia divided less than those activated in atmospheric oxygen, Glut1-Hi lymphocytes exhibited increased effector phenotype acquisition, augmented proliferation, and an inverted CD4/CD8 ratio in both oxygen conditions. Moreover, Glut1-Hi T lymphocytes exhibited a significantly enhanced ability to produce IFN-γ and this secretion potential was completely dependent on continued glycolysis. Thus, Glut1 surface levels identify human T lymphocytes with distinct effector functions in both hypoxic and atmospheric oxygen tensions.
Collapse
|
|
47
|
Gracias DT, Boesteanu AC, Fraietta JA, Hope JL, Carey AJ, Mueller YM, Kawalekar OU, Fike AJ, June CH, Katsikis PD. Phosphatidylinositol 3-Kinase p110δ Isoform Regulates CD8+ T Cell Responses during Acute Viral and Intracellular Bacterial Infections. THE JOURNAL OF IMMUNOLOGY 2016; 196:1186-98. [PMID: 26740110 DOI: 10.4049/jimmunol.1501890] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 12/03/2015] [Indexed: 11/19/2022]
Abstract
The p110δ isoform of PI3K is known to play an important role in immunity, yet its contribution to CTL responses has not been fully elucidated. Using murine p110δ-deficient CD8(+) T cells, we demonstrated a critical role for the p110δ subunit in the generation of optimal primary and memory CD8(+) T cell responses. This was demonstrated in both acute viral and intracellular bacterial infections in mice. We show that p110δ signaling is required for CD8(+) T cell activation, proliferation and effector cytokine production. We provide evidence that the effects of p110δ signaling are mediated via Akt activation and through the regulation of TCR-activated oxidative phosphorylation and aerobic glycolysis. In light of recent clinical trials that employ drugs targeting p110δ in certain cancers and other diseases, our study suggests caution in using these drugs in patients, as they could potentially increase susceptibility to infectious diseases. These studies therefore reveal a novel and direct role for p110δ signaling in in vivo CD8(+) T cell immunity to microbial pathogens.
Collapse
Affiliation(s)
- Donald T Gracias
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Alina C Boesteanu
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Joseph A Fraietta
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104
| | - Jennifer L Hope
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and
| | - Alison J Carey
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Yvonne M Mueller
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and
| | - Omkar U Kawalekar
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104
| | - Adam J Fike
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Carl H June
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104
| | - Peter D Katsikis
- Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129; Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; and
| |
Collapse
|
|
48
|
Ananieva E. Targeting amino acid metabolism in cancer growth and anti-tumor immune response. World J Biol Chem 2015; 6:281-289. [PMID: 26629311 PMCID: PMC4657121 DOI: 10.4331/wjbc.v6.i4.281] [Citation(s) in RCA: 110] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 07/07/2015] [Accepted: 09/30/2015] [Indexed: 02/05/2023] Open
Abstract
Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment, however, tumor cells form metabolic relationships with immune cells, and they often compete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response.
Collapse
|
|
49
|
Wu Y, Deng Z, Tang Y, Zhang S, Zhang YQ. Over-expressing Akt in T cells to resist tumor immunosuppression and increase anti-tumor activity. BMC Cancer 2015; 15:603. [PMID: 26310246 PMCID: PMC4550078 DOI: 10.1186/s12885-015-1611-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Accepted: 08/19/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tumor employs various means to escape immunosurveillance and inhibit immune attack, and strategies have been developed to counteract the inhibitory signals. However, due to the complex suppressive mechanisms in the tumor microenvironment, blocking one or a few inhibitory signals has only limited effects on therapeutic efficacy. Instead of targeting tumor immunosuppression, we considered from another point of view, and hypothesized that manipulating T cells to make them resist any known or unknown suppressive mechanism may be more effective for cancer treatment. METHODS We used OT-1 cells transduced with retroviruses encoding Akt and human peripheral blood lymphocytes (PBLs) transduced with retroviruses encoding both Akt and a chimeric antigen receptor (CAR) specific for tumor antigen EpCAM to examine the effect of over-expressing Akt on tumor specific T cells in tumor environment. RESULTS We show that Akt activity of T cells in the tumor environment was inhibited, and over-expressing Akt in OT-1 cells increased the cytokine production and cell proliferation in the presence of B16-OVA tumor cells. What's more, adoptive transfer of OT-1 cells over-expressing Akt inhibited B16-OVA tumor growth and prolonged mouse survival. To examine if over-expressing Akt could increase the anti-tumor activity of T cells in human cancer, PBLs co-expressing EpCAM specific CAR and Akt were cultured with EpCAM-expressing human prostate cancer cells PC3M, and less inhibition on cell proliferation and less apoptosis were observed. In addition, adoptive transfer of PC3M specific T cells over-expressing Akt resulted in more dramatic tumor inhibitory effects in PC3M bearing NOD/SCID mice. CONCLUSIONS These data indicates that over-expressing Akt in tumor specific T cells increases T cell proliferation and activity in the tumor environment, and enhances anti-tumor effects of adoptively transferred T cells. Our study provides a new strategy to improve the efficacy of adoptive T cell therapy, and serves as an important foundation for clinical translation.
Collapse
Affiliation(s)
- Yanhong Wu
- Department of Immunology, Cancer Hospital & Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100021, China.
| | - Zhenling Deng
- Department of Immunology, Cancer Hospital & Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100021, China.
| | - Yishu Tang
- Department of Immunology, Cancer Hospital & Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100021, China.
| | - Shuren Zhang
- Department of Immunology, Cancer Hospital & Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100021, China.
| | - Yu-Qian Zhang
- Department of Immunology, Cancer Hospital & Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100021, China.
| |
Collapse
|
|
50
|
Chakravarti D, Wong WW. Synthetic biology in cell-based cancer immunotherapy. Trends Biotechnol 2015; 33:449-61. [PMID: 26088008 DOI: 10.1016/j.tibtech.2015.05.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 04/30/2015] [Accepted: 05/06/2015] [Indexed: 12/19/2022]
Abstract
The adoptive transfer of genetically engineered T cells with cancer-targeting receptors has shown tremendous promise for eradicating tumors in clinical trials. This form of cellular immunotherapy presents a unique opportunity to incorporate advanced systems and synthetic biology approaches to create cancer therapeutics with novel functions. We first review the development of synthetic receptors, switches, and circuits to control the location, duration, and strength of T cell activity against tumors. In addition, we discuss the cellular engineering and genome editing of host cells (or the chassis) to improve the efficacy of cell-based cancer therapeutics, and to reduce the time and cost of manufacturing.
Collapse
Affiliation(s)
- Deboki Chakravarti
- Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
| | - Wilson W Wong
- Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
| |
Collapse
|