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Bick F, Blanchetot C, Lambrecht BN, Schuijs MJ. Targeting γc family cytokines with biologics: current status and future prospects. MAbs 2025; 17:2468312. [PMID: 39967341 DOI: 10.1080/19420862.2025.2468312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/07/2025] [Accepted: 02/12/2025] [Indexed: 02/20/2025] Open
Abstract
Over the recent decades the market potential of biologics has substantially expanded, and many of the top-selling drugs worldwide are now monoclonal antibodies or antibody-like molecules. The common gamma chain (γc) cytokines, Interleukin (IL-)2, IL-4, IL-7, IL-9, IL-15, and IL-21, play pivotal roles in regulating immune responses, from innate to adaptive immunity. Dysregulation of cell signaling by these cytokines is strongly associated with a range of immunological disorders, which includes cancer as well as autoimmune and inflammatory diseases. Given the essential role of γc cytokines in maintaining immune homeostasis, the development of therapeutic interventions targeting these molecules poses unique challenges. Here, we provide an overview of current biologics targeting either single or multiple γc cytokines or their respective receptor subunits across a spectrum of diseases, primarily focusing on antibodies, antibody-like constructs, and antibody-cytokine fusions. We summarize therapeutic biologics currently in clinical trials, highlighting how they may offer advantages over existing therapies and standard of care, and discuss recent advances in this field. Finally, we explore future directions and the potential of novel therapeutic intervention strategies targeting this cytokine family.
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Affiliation(s)
- Fabian Bick
- Argenx BV, Zwijnaarde, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | | | - Bart N Lambrecht
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Pulmonary Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Martijn J Schuijs
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
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2
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Li Z, Wrangle J, He K, Sprent J, Rubinstein MP. IL-15: from discovery to FDA approval. J Hematol Oncol 2025; 18:19. [PMID: 39966991 DOI: 10.1186/s13045-025-01664-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Affiliation(s)
- Zihai Li
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, 43210, USA
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - John Wrangle
- Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Kai He
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, 43210, USA
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Jonathan Sprent
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, 2010, Australia
- St. Vincent's Clinical School, University of New South Wales, Sydney, 1466, Australia
| | - Mark P Rubinstein
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, 43210, USA.
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
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Schwartz RR, Seiffert-Sinha K, Sinha AA. Cytokine profiling reveals HLA-linked Th2 and Th17 driven immune activation in pemphigus vulgaris patients and genetically susceptible healthy controls. Front Immunol 2024; 15:1500231. [PMID: 39697331 PMCID: PMC11652493 DOI: 10.3389/fimmu.2024.1500231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/08/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction Cytokines and chemokines direct the inflammatory response and may serve as markers of immune dysregulation in Pemphigus vulgaris (PV), an autoimmune blistering skin disorder. Previous studies on limited numbers of patients and cytokine profiles in PV have produced equivocal results regarding the role these mediators play in disease. Methods In this study, we interrogated serum samples from 116 PV patients and 29 healthy controls by multiplexed bead array assays across a comprehensive set of cytokines and chemokines covering several functional categories, including IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, IL-21, IL-22, IL-23, TNFα, IFNγ, MCP-1, and Eotaxin. Results We found that patients with PV generally display an activated cytokine and chemokine immune response compared to controls, but also show remarkable interindividual heterogeneity in terms of cytokine levels, with a limited activation of different T helper cell pathways in different patients. Surprisingly, we also found that healthy individuals that carry the PV susceptibility alleles HLA DR4 (DRB1*0402) and/or DR6 (DQB1*0503) (HLA-matched controls) show an upregulation of cytokine and chemokine levels that are on par with those seen in PV patients for certain pro-inflammatory, Th2, and Th17 mediators and IL-8, while healthy controls that did not carry the PV susceptibility alleles (HLA-unmatched controls) express significantly lower levels of these cytokines and chemokines. Discussion Our data suggest the existence of a limited immune activation linked to the presence of key PV associated HLA alleles regardless of disease status. Interestingly, the cytokines IL-10 and IL-15 were found to be significantly downregulated in the HLA-matched control group, suggesting the presence of a possible counter-regulatory function in genetically susceptible but disease-free individuals.
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Affiliation(s)
| | | | - Animesh A. Sinha
- Department of Dermatology, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, United States
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Scapin G, Cagdas E, Grav LM, Lewis NE, Goletz S, Hafkenscheid L. Implications of glycosylation for the development of selected cytokines and their derivatives for medical use. Biotechnol Adv 2024; 77:108467. [PMID: 39447666 DOI: 10.1016/j.biotechadv.2024.108467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 09/13/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
Cytokines are important regulators of immune responses, making them attractive targets for autoimmune diseases and cancer therapeutics. Yet, the significance of cytokine glycosylation remains underestimated. Many cytokines carry N- and O-glycans and some even undergo C-mannosylation. Recombinant cytokines produced in heterologous host cells may lack glycans or exhibit a different glycosylation pattern such as varying levels of galactosylation, sialylation, fucosylation or xylose addition compared to their human counterparts, potentially impacting critical immune interactions. We focused on cytokines that are currently utilized or designed in advanced therapeutic formats, including immunocytokines, fusokines, engager cytokines, and genetically engineered 'supercytokines.' Despite the innovative designs of these cytokine derivatives, their glycosylation patterns have not been extensively studied. By examining the glycosylation of the human native cytokines, G-CSF and GM-CSF, interferons β and γ, TNF-α and interleukins-2, -3 -4, -6, -7, -9, -12, -13, -15, -17A, -21, and - 22, we aim to assess its potential impact on their therapeutic derivatives. Understanding the glycosylation of the native cytokines could provide critical insights into the safety, efficacy, and functionality of these next-generation cytokine therapies, affecting factors such as stability, bioactivity, antigenicity, and half-life. This knowledge can guide the choice of optimal expression hosts for production and advance the development of effective cytokine-based therapeutics and synthetic immunology drugs.
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Affiliation(s)
- Giulia Scapin
- Department of Biotechnology and Biomedicine, Mammalian Cell Line Engineering, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark
| | - Ece Cagdas
- Department of Biotechnology and Biomedicine, Mammalian Cell Line Engineering, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark
| | - Lise Marie Grav
- Department of Biotechnology and Biomedicine, Mammalian Cell Line Engineering, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark; The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark
| | - Nathan E Lewis
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Steffen Goletz
- Department of Biotechnology and Biomedicine, Biotherapeutic Glycoengineering and Immunology, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark.
| | - Lise Hafkenscheid
- Department of Biotechnology and Biomedicine, Biotherapeutic Glycoengineering and Immunology, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark.
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Chen S, Zhu H, Jounaidi Y. Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization. Signal Transduct Target Ther 2024; 9:302. [PMID: 39511139 PMCID: PMC11544004 DOI: 10.1038/s41392-024-02005-w] [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: 05/19/2024] [Revised: 08/25/2024] [Accepted: 09/17/2024] [Indexed: 11/15/2024] Open
Abstract
Natural killer (NK) cells, initially identified for their rapid virus-infected and leukemia cell killing and tumor destruction, are pivotal in immunity. They exhibit multifaceted roles in cancer, viral infections, autoimmunity, pregnancy, wound healing, and more. Derived from a common lymphoid progenitor, they lack CD3, B-cell, or T-cell receptors but wield high cytotoxicity via perforin and granzymes. NK cells orchestrate immune responses, secreting inflammatory IFNγ or immunosuppressive TGFβ and IL-10. CD56dim and CD56bright NK cells execute cytotoxicity, while CD56bright cells also regulate immunity. However, beyond the CD56 dichotomy, detailed phenotypic diversity reveals many functional subsets that may not be optimal for cancer immunotherapy. In this review, we provide comprehensive and detailed snapshots of NK cells' functions and states of activation and inhibitions in cancer, autoimmunity, angiogenesis, wound healing, pregnancy and fertility, aging, and senescence mediated by complex signaling and ligand-receptor interactions, including the impact of the environment. As the use of engineered NK cells for cancer immunotherapy accelerates, often in the footsteps of T-cell-derived engineering, we examine the interactions of NK cells with other immune effectors and relevant signaling and the limitations in the tumor microenvironment, intending to understand how to enhance their cytolytic activities specifically for cancer immunotherapy.
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Affiliation(s)
- Sumei Chen
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China.
| | - Haitao Zhu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Youssef Jounaidi
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Duan Z, Yang Y, Qin M, Yi X. Interleukin 15: A new intermediary in the effects of exercise and training on skeletal muscle and bone function. J Cell Mol Med 2024; 28:e70136. [PMID: 39601091 PMCID: PMC11599876 DOI: 10.1111/jcmm.70136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 09/26/2024] [Accepted: 10/01/2024] [Indexed: 11/29/2024] Open
Abstract
Interleukin-15 (IL-15), a pro-inflammatory cytokine, is produced mainly by skeletal muscle cells, macrophages and epithelial cells. Recent research has demonstrated that IL-15 is closely related to the functions of bone and skeletal muscle in the locomotor system. There is growing evidence that exercise, an important means to regulate the immune and locomotor systems, influences IL-15 content in various tissues, thereby indirectly affecting the function of bones and muscles. Furthermore, the form, intensity, and duration of exercise determine the degree of change in IL-15 and downstream effects. This paper reviews the structure, synthesis and secretion of IL-15, the role of IL-15 in regulating the metabolism of bone tissue cells and myofibers through binding to the IL-15 receptor-α (IL-15Rα), and the response of IL-15 to different types of exercise. This review provides a reference for further analyses of the role and mechanism of action of IL-15 in the regulation of metabolism during exercise.
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Affiliation(s)
- Ziqiang Duan
- School of Sports HealthShenyang Sport UniversityShenyangChina
| | - Yang Yang
- School of KinesiologyShanghai University of SportShanghaiChina
| | - Mianhong Qin
- School of Sports HealthShenyang Sport UniversityShenyangChina
| | - Xuejie Yi
- Social Science Research CenterShenyang Sport UniversityShenyangChina
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Wang H, Yang J, Sun Z, Nie Y, He Y. Neoprzewaquinone A alters the migration, phagocytosis and energy metabolism of IL-15-induced HMC3 cells. Mol Immunol 2024; 174:11-17. [PMID: 39128414 DOI: 10.1016/j.molimm.2024.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/16/2024] [Accepted: 07/29/2024] [Indexed: 08/13/2024]
Abstract
Microglia play a major role in the immune defense system of the central nervous system and are activated in many neurological diseases. The immunomodulatory cytokine interleukin (IL)-15 is known to be involved in microglia response and inflammatory factors release. Neoprzewaquinone A (NEO) is an active compound isolated from Salvia miltiorrhiza Bunge. Our previous study has shown that NEO significantly inhibit the proliferation of IL-15-treated Mo7e cells. However, the role of NEO in the structure and function of IL-15-treated human microglial cells (HMC3) remains unclear. Thus, our study aimed to quantitatively analyze the beneficial effects of NEO on HMC3 cells following IL-15 treatment. The cell viability, phagocytosis, migration and energy metabolism were evaluated by Cell Counting Kit-8 (CCK8), scratch assay, pHrodo™ Red Zymosan BioParticles™ Conjugate, and Agilent Seahorse XF Cell Mito Test. Cephalothin (CEP) was selected as a positive drug because it has obvious inhibitory effect on IL-15 and IL-15Rɑ. Our results showed that IL-15 stimulated the proliferation, migration and phagocytosis of HMC3 cells in a time-dependent manner. Interestingly, NEO exhibited significant suppressive effects on these IL-15-induced changes, which were even superior to those observed with the CEP. Moreover, IL-15 treatment did not significantly alter energy metabolism, including glycolysis and mitochondrial respiration. NEO and CEP alone effectively reduced glycolysis, non-mitochondrial respiration, basal respiration, ATP turnover, respiration capacity, and H+ leak in HMC3 cells. Furthermore, NEO displayed a partial regulatory effect on mitochondrial function in IL-15-treated HMC3 cells. Our study confirms the effectively inhibition of NEO on IL-15-induced microglial activation and provides valuable insights into the therapeutic prospects of NEO in neuropsychiatric disorders associated with IL-15 and microglia.
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Affiliation(s)
- Haixia Wang
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China
| | - Jian Yang
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China
| | - Zuoli Sun
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China
| | - Yadan Nie
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China
| | - Yi He
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China.
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8
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Li J, Clark R, Slaga D, Avery K, Liu K, Schubbert S, Varma R, Chiang E, Totpal K, Bernett MJ, Holder PG, Junttila TT. IL-15/IL-15Rα-Fc-Fusion Protein XmAb24306 Potentiates Activity of CD3 Bispecific Antibodies through Enhancing T-Cell Expansion. Mol Cancer Ther 2024; 23:1305-1316. [PMID: 38739434 DOI: 10.1158/1535-7163.mct-23-0910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/26/2024] [Accepted: 04/26/2024] [Indexed: 05/14/2024]
Abstract
An insufficient quantity of functional T cells is a likely factor limiting the clinical activity of T-cell bispecific antibodies, especially in solid tumor indications. We hypothesized that XmAb24306 (efbalropendekin alfa), a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein, may potentiate the activity of T-cell dependent (TDB) antibodies. The activation of human peripheral T cells by cevostamab, an anti-FcRH5/CD3 TDB, or anti-HER2/CD3 TDB resulted in the upregulation of the IL-2/15Rβ (CD122) receptor subunit in nearly all CD8+ and majority of CD4+ T cells, suggesting that TDB treatment may sensitize T cells to IL-15. XmAb24306 enhanced T-cell bispecific antibody-induced CD8+ and CD4+ T-cell proliferation and expansion. In vitro combination of XmAb24306 with cevostamab or anti-HER2/CD3 TDB resulted in significant enhancement of tumor cell killing, which was reversed when T-cell numbers were normalized, suggesting that T-cell expansion is the main mechanism of the observed benefit. Pretreatment of immunocompetent mice with a mouse-reactive surrogate of XmAb24306 (mIL-15-Fc) resulted in a significant increase of T cells in the blood, spleen, and tumors and converted transient anti-HER2/CD3 TDB responses to complete durable responses. In summary, our results support the hypothesis that the number of tumor-infiltrating T cells is rate limiting for the activity of solid tumor-targeting TDBs. Upregulation of CD122 by TDB treatment and the observed synergy with XmAb24306 and T-cell bispecific antibodies support clinical evaluation of this novel immunotherapy combination.
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Affiliation(s)
- Ji Li
- Genentech Inc., South San Francisco, California
| | - Robyn Clark
- Genentech Inc., South San Francisco, California
| | | | | | - Ke Liu
- Xencor Inc., Pasadena, California
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Fatima T, Mubasher MM, Rehman HM, Niyazi S, Alanzi AR, Kalsoom M, Khalid S, Bashir H. Computational modeling study of IL-15-NGR peptide fusion protein: a targeted therapeutics for hepatocellular carcinoma. AMB Express 2024; 14:91. [PMID: 39133343 PMCID: PMC11319546 DOI: 10.1186/s13568-024-01747-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/25/2024] [Indexed: 08/13/2024] Open
Abstract
The primary challenge to improving existing cancer treatment is to develop drugs that specifically target tumor cell. NGR peptide is tumor homing peptide that selectively target cancer cells while interleukin 15 is a pleiotropic cytokine with anticancer properties. This study computationally engineered a IL15-NGR fusion peptide by linking the homing peptide NGR with the targeting peptide IL-15. After evaluating and validating the chimeric peptide, we docked it to the IL-15Rα/IL-15Rβ/γc heterodimer receptor, examining the interactions and binding energy and lastly, molecular dynamics simulations were performed. The secondary and tertiary structures, along with physicochemical properties of the designed IL-15-NGR chimeric protein, were predicted using GOR IV, trRosetta and ProtParam online servers respectively. The quality and 3D structure validation were confirmed via ProSA-web and SAVES 6.0 analysis which predicted an ERRAT score of 96.72%, with 97.6% of residues in the Ramachandran plot, validating its structure. Finally, Docking, MD simulations and interaction analysis were performed using ClusPro 2.0 and GROMACS and PDBsum, which exhibited significant hydrogen bonding and salt bridges, confirming the formation of a stable docked complex. These results were further corroborated by simulation analysis, which demonstrated a stable and dynamic behavior of the docked complex in a biological environment. The predicted high expression value of fusion protein was 0.844 in E.coli using SOLUPROT tool. These findings suggest efficient expression of the IL15-NGR fusion protein if its gene is inserted into E. coli and indicates its potential as a safe and effective anticancer treatment, paving the way for targeted therapeutic interventions.
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Affiliation(s)
- Tehreem Fatima
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan
| | | | - Hafiz Muhammad Rehman
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan.
- University Institute of Medical Lab Technology, Faculty of Allied health sciences, The University of Lahore, Lahore, 54590, Pakistan.
| | - Sakina Niyazi
- School of Biotechnology, IFTM University, Moradabad, 244102, India
| | - Abdullah R Alanzi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Maria Kalsoom
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan
| | - Sania Khalid
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan
| | - Hamid Bashir
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan.
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Shi J, Wu W, Chen D, Liao Z, Sheng T, Wang Y, Yao Y, Wu Q, Liu F, Zhou R, Zhu C, Shen X, Mao Z, Ding Y, Wang W, Dotti G, Sun J, Liang X, Fang W, Zhao P, Li H, Gu Z. Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells. NATURE MATERIALS 2024; 23:844-853. [PMID: 38448658 DOI: 10.1038/s41563-024-01825-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 01/31/2024] [Indexed: 03/08/2024]
Abstract
Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.
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Affiliation(s)
- Jiaqi Shi
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Wei Wu
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dong Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ziyan Liao
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Tao Sheng
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yanfang Wang
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yuejun Yao
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qing Wu
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Feng Liu
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Ruyi Zhou
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Chaojie Zhu
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xinyuan Shen
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Zhengwei Mao
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
| | - Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Gianpietro Dotti
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Jie Sun
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Peng Zhao
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Hongjun Li
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Jinhua Institute, Zhejiang University, Jinhua, China.
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
| | - Zhen Gu
- National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China.
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Jinhua Institute, Zhejiang University, Jinhua, China.
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
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Vahidi S, Zabeti Touchaei A, Samadani AA. IL-15 as a key regulator in NK cell-mediated immunotherapy for cancer: From bench to bedside. Int Immunopharmacol 2024; 133:112156. [PMID: 38669950 DOI: 10.1016/j.intimp.2024.112156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/04/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
Interleukin 15 (IL-15) has emerged as a crucial factor in the relationship between natural killer (NK) cells and immunotherapy for cancer. This review article aims to provide a comprehensive understanding of the role of IL-15 in NK cell-mediated immunotherapy. First, the key role of IL-15 signaling in NK cell immunity is discussed, highlighting its regulation of NK cell functions and antitumor properties. Furthermore, the use of IL-15 or its analogs in clinical trials as a therapeutic strategy for various cancers, including the genetic modification of NK cells to produce IL-15, has been explored. The potential of IL-15-based therapies, such as chimeric antigen receptor (CAR) T and NK cell infusion along with IL-15 in combination with checkpoint inhibitors and other treatments, has been examined. This review also addresses the challenges and advantages of incorporating IL-15 in cell-based immunotherapy. Additionally, unresolved questions regarding the detection and biological significance of the soluble IL-15/IL-15Rα complex, as well as the potential role of IL-15/IL-15Rα in human cancer and the immunological consequences of prolonged exposure to soluble IL-15 for NK cells, are discussed.
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Affiliation(s)
- Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | | | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran.
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12
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Ren Z, Zhang X, Fu YX. Facts and Hopes on Chimeric Cytokine Agents for Cancer Immunotherapy. Clin Cancer Res 2024; 30:2025-2038. [PMID: 38190116 DOI: 10.1158/1078-0432.ccr-23-1160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/17/2023] [Accepted: 12/27/2023] [Indexed: 01/09/2024]
Abstract
Cytokines are key mediators of immune responses that can modulate the antitumor activity of immune cells. Cytokines have been explored as a promising cancer immunotherapy. However, there are several challenges to cytokine therapy, especially a lack of tumor targeting, resulting in high toxicity and limited efficacy. To overcome these limitations, novel approaches have been developed to engineer cytokines with improved properties, such as chimeric cytokines. Chimeric cytokines are fusion proteins that combine different cytokine domains or link cytokines to antibodies (immunocytokines) or other molecules that can target specific receptors or cells. Chimeric cytokines can enhance the selectivity and stability of cytokines, leading to reduced toxicity and improved efficacy. In this review, we focus on two promising cytokines, IL2 and IL15, and summarize the current advances and challenges of chimeric cytokine design and application for cancer immunotherapy. Most of the current approaches focus on increasing the potency of cytokines, but another important goal is to reduce toxicity. Cytokine engineering is promising for cancer immunotherapy as it can enhance tumor targeting while minimizing adverse effects.
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Affiliation(s)
| | - Xuhao Zhang
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Yang-Xin Fu
- Changping Laboratory, Beijing, China
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
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13
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Fang KM, Chiu YL, Hong RW, Cheng PC, Cheng PW, Liao LJ. The Interleukin-15 and Interleukin-8 Axis as a Novel Mechanism for Recurrent Chronic Rhinosinusitis with Nasal Polyps. Biomedicines 2024; 12:980. [PMID: 38790942 PMCID: PMC11117578 DOI: 10.3390/biomedicines12050980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 04/22/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
The prevention of postoperative recurrence after endoscopic sinus surgery (ESS) relies on targeting specific pathological mechanisms according to individuals' immunological profiles. However, essential biomarkers and biological characteristics of difficult-to-treat chronic rhinosinusitis (CRS) patients are not well-defined. The aim of this study was to explore the immunologic profiles of subgroups of CRS patients and determine the specific cytokines responsible for recalcitrant or recurrent CRS with nasal polyposis (rCRSwNP). We used 30 cytokine antibody arrays to determine the key cytokines related to recurrent polypogenesis. Enzyme-linked immunosorbent assay (ELISA) experiments were conducted to assess the levels of these key cytokines in 78 patients. Polymorphonuclear leukocytes (PMNs) isolated from nasal polyps were challenged with specific cytokines to examine the levels of enhanced interleukin (IL)-8 production. Finally, we used immunohistochemistry (IHC) staining to check for the presence and distribution of the biomarkers within nasal polyps. A cytokine antibody array revealed that IL-8, IL-13, IL-15, and IL-20 were significantly higher in the recalcitrant CRSwNP group. Subsequent ELISA screening showed a stepwise increase in tissue IL-8 levels in the CHR, CRSsNP, and CRSwNP groups. PMNs isolated from nine CRSwNP cases all demonstrated enhanced IL-8 production after IL-15 treatment. IHC staining was labeled concurrent IL-8 and IL-15 expression in areas of prominent neutrophil infiltration. Our results suggest that IL-15 within the sinonasal mucosa plays a crucial role in promoting IL-8 secretion by infiltrating PMNs in recalcitrant nasal polyps. In addition, we propose a novel therapeutic strategy targeting the anti-IL-15/IL-8 axis to treat CRS with nasal polyposis.
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Affiliation(s)
- Kai-Min Fang
- Department of Nursing, Oriental Institute of Technology, College of Healthcare and Management, New Taipei City 220, Taiwan;
- Department of Otolaryngology Head and Neck Surgery, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan; (P.-C.C.); (P.-W.C.)
| | - Yen-Ling Chiu
- Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan; (Y.-L.C.); (R.-W.H.)
| | - Ruo-Wei Hong
- Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan; (Y.-L.C.); (R.-W.H.)
| | - Ping-Chia Cheng
- Department of Otolaryngology Head and Neck Surgery, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan; (P.-C.C.); (P.-W.C.)
| | - Po-Wen Cheng
- Department of Otolaryngology Head and Neck Surgery, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan; (P.-C.C.); (P.-W.C.)
| | - Li-Jen Liao
- Department of Otolaryngology Head and Neck Surgery, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan; (P.-C.C.); (P.-W.C.)
- Department of Electrical Engineering, Yuan Ze University, Taoyuan 320, Taiwan
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14
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Ullah F, Markouli M, Orland M, Ogbue O, Dima D, Omar N, Mustafa Ali MK. Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment. Cancers (Basel) 2024; 16:1307. [PMID: 38610985 PMCID: PMC11011145 DOI: 10.3390/cancers16071307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disorder characterized by persistent clonal expansion of mature T- or natural killer cells in the blood via chronic antigenic stimulation. LGL leukemia is associated with specific immunophenotypic and molecular features, particularly STAT3 and STAT5 mutations and activation of the JAK-STAT3, Fas/Fas-L and NF-κB signaling pathways. Disease-related deaths are mainly due to recurrent infections linked to severe neutropenia. The current treatment is based on immunosuppressive therapies, which frequently produce unsatisfactory long-term responses, and for this reason, personalized approaches and targeted therapies are needed. Here, we discuss molecular pathogenesis, clinical presentation, associated autoimmune disorders, and the available treatment options, including emerging therapies.
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Affiliation(s)
- Fauzia Ullah
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; (M.O.); (O.O.); (D.D.); (N.O.); (M.K.M.A.)
| | - Mariam Markouli
- Department of Internal Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Mark Orland
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; (M.O.); (O.O.); (D.D.); (N.O.); (M.K.M.A.)
| | - Olisaemeka Ogbue
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; (M.O.); (O.O.); (D.D.); (N.O.); (M.K.M.A.)
| | - Danai Dima
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; (M.O.); (O.O.); (D.D.); (N.O.); (M.K.M.A.)
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44915, USA
| | - Najiullah Omar
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; (M.O.); (O.O.); (D.D.); (N.O.); (M.K.M.A.)
| | - Moaath K. Mustafa Ali
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; (M.O.); (O.O.); (D.D.); (N.O.); (M.K.M.A.)
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44915, USA
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15
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Stenger TD, Miller JS. Therapeutic approaches to enhance natural killer cell cytotoxicity. Front Immunol 2024; 15:1356666. [PMID: 38545115 PMCID: PMC10966407 DOI: 10.3389/fimmu.2024.1356666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 02/05/2024] [Indexed: 04/14/2024] Open
Abstract
Enhancing the cytotoxicity of natural killer (NK) cells has emerged as a promising strategy in cancer immunotherapy, due to their pivotal role in immune surveillance and tumor clearance. This literature review provides a comprehensive overview of therapeutic approaches designed to augment NK cell cytotoxicity. We analyze a wide range of strategies, including cytokine-based treatment, monoclonal antibodies, and NK cell engagers, and discuss criteria that must be considered when selecting an NK cell product to combine with these strategies. Furthermore, we discuss the challenges and limitations associated with each therapeutic strategy, as well as the potential for combination therapies to maximize NK cell cytotoxicity while minimizing adverse effects. By exploring the wealth of research on this topic, this literature review aims to provide a comprehensive resource for researchers and clinicians seeking to develop and implement novel therapeutic strategies that harness the full potential of NK cells in the fight against cancer. Enhancing NK cell cytotoxicity holds great promise in the evolving landscape of immunotherapy, and this review serves as a roadmap for understanding the current state of the field and the future directions in NK cell-based therapies.
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Affiliation(s)
- Terran D. Stenger
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
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16
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Hall G. Interleukin-15 in kidney disease and therapeutics. Curr Opin Nephrol Hypertens 2024; 33:174-180. [PMID: 38164877 PMCID: PMC10893218 DOI: 10.1097/mnh.0000000000000964] [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] [Indexed: 01/03/2024]
Abstract
PURPOSE OF REVIEW Interleukin 15 (IL-15) is a member of the IL-2 family of common gamma chain receptor cytokines with well described anti-inflammatory, pro-survival and pro-proliferative signaling properties. The cytoprotective role of IL-15 in the kidney is now coming into focus with recent reports of its beneficial actions in various forms of kidney disease. This review will summarize what is currently known about IL-15 signaling in the kidney and highlight recent evidence of its beneficial effects on kidney physiology. RECENT FINDINGS IL-15 and its heterotrimeric receptor are expressed throughout the kidney. Like all IL-2 family cytokines, IL-15 can activate signaling through the Janus Kinase (JAK)/Signal transducer of activated T-cells (STAT), phosphoinositol-3 kinase (PI-3K)/AKT and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways and recent evidence suggests that STAT5B is an essential transcriptional mediator of prosurvival signaling in glomerular visceral epithelial cells (i.e. podocytes). IL-15 has also been shown to suppress pro-apoptotic signaling in models of acute kidney injury and pro-fibrotic signaling in models of chronic kidney disease. SUMMARY The cytoprotective properties of IL-15 suggest that it may have potential as a nonimmunosuppresive therapeutic for kidney disease. A novel class of IL-15 immunotherapies has emerged for the treatment cancer and some have demonstrated efficacy in clinical trials. These well tolerated IL-15 agonists could possibly be repurposed for the treatment of kidney disease and warrant further exploration.
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Affiliation(s)
- Gentzon Hall
- Division of Nephrology, Duke University, Durham, North Carolina, USA
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17
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Rahmati M, Haffner M, Lee MA, Leach JK, Saiz AM. The critical impact of traumatic muscle loss on fracture healing: Basic science and clinical aspects. J Orthop Res 2024; 42:249-258. [PMID: 37990953 DOI: 10.1002/jor.25746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/05/2023] [Accepted: 11/20/2023] [Indexed: 11/23/2023]
Abstract
Musculoskeletal trauma, specifically fractures, is a leading cause of patient morbidity and disability worldwide. In approximately 20% of cases with fracture and related traumatic muscle loss, bone healing is impaired leading to fracture nonunion. Over the past few years, several studies have demonstrated that bone and the surrounding muscle tissue interact not only anatomically and mechanically but also through biochemical pathways and mediators. Severe damage to the surrounding musculature at the fracture site causes an insufficiency in muscle-derived osteoprogenitor cells that are crucial for fracture healing. As an endocrine tissue, skeletal muscle produces many myokines that act on different bone cells, such as osteoblasts, osteoclasts, osteocytes, and mesenchymal stem cells. Investigating how muscle influences fracture healing at cellular, molecular, and hormonal levels provides translational therapeutic solutions to this clinical challenge. This review provides an overview about the contributions of surrounding muscle tissue in directing fracture healing. The focus of the review is on describing the interactions between bone and muscle in both healthy and fractured environments. We discuss current progress in identifying the bone-muscle molecular pathways and strategies to harness these pathways as cues for accelerating fracture healing. In addition, we review the existing challenges and research opportunities in the field.
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Affiliation(s)
- Maryam Rahmati
- Department of Orthopaedic Surgery, University of California, Davis, Sacramento, California, USA
| | - Max Haffner
- Department of Orthopaedic Surgery, University of California, Davis, Sacramento, California, USA
| | - Mark A Lee
- Department of Orthopaedic Surgery, University of California, Davis, Sacramento, California, USA
| | - Jonathan Kent Leach
- Department of Orthopaedic Surgery, University of California, Davis, Sacramento, California, USA
- Department of Biomedical Engineering, University of California, Davis, Davis, California, USA
| | - Augustine M Saiz
- Department of Orthopaedic Surgery, University of California, Davis, Sacramento, California, USA
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18
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Lee H, Park SH, Shin EC. IL-15 in T-Cell Responses and Immunopathogenesis. Immune Netw 2024; 24:e11. [PMID: 38455459 PMCID: PMC10917573 DOI: 10.4110/in.2024.24.e11] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/01/2024] [Accepted: 02/01/2024] [Indexed: 03/09/2024] Open
Abstract
IL-15 belongs to the common gamma chain cytokine family and has pleiotropic immunological functions. IL-15 is a homeostatic cytokine essential for the development and maintenance of NK cells and memory CD8+ T cells. In addition, IL-15 plays a critical role in the activation, effector functions, tissue residency, and senescence of CD8+ T cells. IL-15 also activates virtual memory T cells, mucosal-associated invariant T cells and γδ T cells. Recently, IL-15 has been highlighted as a major trigger of TCR-independent activation of T cells. This mechanism is involved in T cell-mediated immunopathogenesis in diverse diseases, including viral infections and chronic inflammatory diseases. Deeper understanding of IL-15-mediated T-cell responses and their underlying mechanisms could optimize therapeutic strategies to ameliorate host injury by T cell-mediated immunopathogenesis. This review highlights recent advancements in comprehending the role of IL-15 in relation to T cell responses and immunopathogenesis under various host conditions.
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Affiliation(s)
- Hoyoung Lee
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Eui-Cheol Shin
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Korea
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
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19
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Skariah N, James OJ, Swamy M. Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes. DISCOVERY IMMUNOLOGY 2024; 3:kyae002. [PMID: 38405398 PMCID: PMC10883678 DOI: 10.1093/discim/kyae002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/19/2023] [Accepted: 01/26/2024] [Indexed: 02/27/2024]
Abstract
There is an intriguing dichotomy in the function of cytokine interleukin-15-at low levels, it is required for the homeostasis of the immune system, yet when it is upregulated in response to pathogenic infections or in autoimmunity, IL-15 drives inflammation. IL-15 associates with the IL-15Rα within both myeloid and non-haematopoietic cells, where IL-15Rα trans-presents IL-15 in a membrane-bound form to neighboring cells. Alongside homeostatic maintenance of select lymphocyte populations such as NK cells and tissue-resident T cells, when upregulated, IL-15 also promotes inflammatory outcomes by driving effector function and cytotoxicity in NK cells and T cells. As chronic over-expression of IL-15 can lead to autoimmunity, IL-15 expression is tightly regulated. Thus, blocking dysregulated IL-15 and its downstream signalling pathways are avenues for immunotherapy. In this review we discuss the molecular pathways involved in IL-15 signalling and how these pathways contribute to both homeostatic and inflammatory functions in IL-15-dependent mature lymphoid populations, focusing on innate, and innate-like lymphocytes in tissues.
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Affiliation(s)
- Neema Skariah
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Olivia J James
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Mahima Swamy
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
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20
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Dean I, Lee CYC, Tuong ZK, Li Z, Tibbitt CA, Willis C, Gaspal F, Kennedy BC, Matei-Rascu V, Fiancette R, Nordenvall C, Lindforss U, Baker SM, Stockmann C, Sexl V, Hammond SA, Dovedi SJ, Mjösberg J, Hepworth MR, Carlesso G, Clatworthy MR, Withers DR. Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity. Nat Commun 2024; 15:683. [PMID: 38267402 PMCID: PMC10808449 DOI: 10.1038/s41467-024-44789-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 01/02/2024] [Indexed: 01/26/2024] Open
Abstract
Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.
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Affiliation(s)
- Isaac Dean
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Colin Y C Lee
- Department of Medicine, Molecular Immunity Unit, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK
- Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Zewen K Tuong
- Department of Medicine, Molecular Immunity Unit, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK
- Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Zhi Li
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Christopher A Tibbitt
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Claire Willis
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Fabrina Gaspal
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Bethany C Kennedy
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Veronika Matei-Rascu
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Rémi Fiancette
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Caroline Nordenvall
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Pelvic Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Ulrik Lindforss
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Pelvic Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Syed Murtuza Baker
- Division of Informatics, Imaging & Data Science, Faculty of Biology, Medicine and Health, the University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | | | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | | | | | - Jenny Mjösberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Clinical Lung and Allergy Research, Medical unit for Lung and Allergy Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Matthew R Hepworth
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, the University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | | | - Menna R Clatworthy
- Department of Medicine, Molecular Immunity Unit, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK.
- Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
| | - David R Withers
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
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21
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Khalafi M, Maleki AH, Symonds ME, Sakhaei MH, Rosenkranz SK, Ehsanifar M, Korivi M, Liu Y. Interleukin-15 responses to acute and chronic exercise in adults: a systematic review and meta-analysis. Front Immunol 2024; 14:1288537. [PMID: 38235143 PMCID: PMC10791876 DOI: 10.3389/fimmu.2023.1288537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 12/11/2023] [Indexed: 01/19/2024] Open
Abstract
Purpose Interlukin-15 (IL-15) is an inflammatory cytokine that plays a vital role in immunology and obesity-associated metabolic syndrome. We performed this systematic review and meta-analysis to investigate whether exercise promotes circulating IL-15 concentrations in adults. Methods We searched PubMed, Web of Science, and Scopus from inception to May, 2023 and identified original studies that investigated the effectiveness of acute and/or chronic exercise on serum/plasma IL-15 levels in adults. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated using random effect models. Subgroup analyses were performed based on type of exercise, and training status, health status and body mass indexes (BMI) of participants. Results Fifteen studies involving 411 participants and 12 studies involving 899 participants were included in the acute and chronic exercise analyses, respectively. Our findings showed that acute exercise increased circulating IL-15 concentrations immediately after exercise compared with baseline [SMD=0.90 (95% CI: 0.47 to 1.32), p=0.001], regardless of exercise type and participants' training status. Similarly, acute exercise was also associated with increased IL-15 concentrations even one-hour after exercise [SMD=0.50 (95% CI: 0.00 to 0.99), p=0.04]. Nevertheless, chronic exercise did not have a significant effect on IL-15 concentrations [SMD=0.40 (95% CI: -0.08 to 0.88), p=0.10]. Conclusion Our results confirm that acute exercise is effective in increasing the IL-15 concentrations immediately and one-hour after exercise intervention, and thereby playing a potential role in improving metabolism in adults. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=445634, identifier CRD42023445634.
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Affiliation(s)
- Mousa Khalafi
- Department of Physical Education and Sport Sciences, Faculty of Humanities, University of Kashan, Kashan, Iran
| | - Aref Habibi Maleki
- Department of Exercise Physiology and Corrective Exercises, Faculty of Sport Sciences, Urmia University, Urmia, Iran
| | - Michael E. Symonds
- Academic Unit of Population and Lifespan Sciences, Centre for Perinatal Research, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Mohammad Hossein Sakhaei
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Guilan, Guilan, Iran
| | - Sara K. Rosenkranz
- Department of Kinesiology and Nutrition Sciences, University of Nevada Las Vegas, Las Vegas, NV, United States
| | - Mahsa Ehsanifar
- Department of Exercise Physiology and Corrective Exercises, Faculty of Sport Sciences, Urmia University, Urmia, Iran
| | - Mallikarjuna Korivi
- Institute of Human Movement and Sports Engineering, Zhejiang Normal University, Jinhua, Zhejiang, China
| | - Yubo Liu
- Institute of Human Movement and Sports Engineering, Zhejiang Normal University, Jinhua, Zhejiang, China
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22
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Martin-Salgado M, Ochoa-Echeverría A, Mérida I. Diacylglycerol kinases: A look into the future of immunotherapy. Adv Biol Regul 2024; 91:100999. [PMID: 37949728 DOI: 10.1016/j.jbior.2023.100999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023]
Abstract
Cancer still represents the second leading cause of death right after cardiovascular diseases. According to the World Health Organization (WHO), cancer provoked around 10 million deaths in 2020, with lung and colon tumors accounting for the deadliest forms of cancer. As tumor cells become resistant to traditional therapeutic approaches, immunotherapy has emerged as a novel strategy for tumor control. T lymphocytes are key players in immune responses against tumors. Immunosurveillance allows identification, targeting and later killing of cancerous cells. Nevertheless, tumors evolve through different strategies to evade the immune response and spread in a process called metastasis. The ineffectiveness of traditional strategies to control tumor growth and expansion has led to novel approaches considering modulation of T cell activation and effector functions. Program death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) showed promising results in the early 90s and nowadays are still being exploited together with other drugs for several cancer types. Other negative regulators of T cell activation are diacylglycerol kinases (DGKs) a family of enzymes that catalyze the conversion of diacylglycerol (DAG) into phosphatidic acid (PA). In T cells, DGKα and DGKζ limit the PLCγ/Ras/ERK axis thus attenuating DAG mediated signaling and T cell effector functions. Upregulation of either of both isoforms results in impaired Ras activation and anergy induction, whereas germline knockdown mice showed enhanced antitumor properties and more effective immune responses against pathogens. Here we review the mechanisms used by DGKs to ameliorate T cell activation and how inhibition could be used to reinvigorate T cell functions in cancer context. A better knowledge of the molecular mechanisms involved upon T cell activation will help to improve current therapies with DAG promoting agents.
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Affiliation(s)
- Miguel Martin-Salgado
- Department of Immunology and Oncology. National Centre for Biotechnology. Spanish Research Council (CNB-CSIC), Spain
| | - Ane Ochoa-Echeverría
- Department of Immunology and Oncology. National Centre for Biotechnology. Spanish Research Council (CNB-CSIC), Spain
| | - Isabel Mérida
- Department of Immunology and Oncology. National Centre for Biotechnology. Spanish Research Council (CNB-CSIC), Spain.
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23
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Luo M, Gong W, Zhang Y, Li H, Ma D, Wu K, Gao Q, Fang Y. New insights into the stemness of adoptively transferred T cells by γc family cytokines. Cell Commun Signal 2023; 21:347. [PMID: 38049832 PMCID: PMC10694921 DOI: 10.1186/s12964-023-01354-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/11/2023] [Indexed: 12/06/2023] Open
Abstract
T cell-based adoptive cell therapy (ACT) has exhibited excellent antitumoral efficacy exemplified by the clinical breakthrough of chimeric antigen receptor therapy (CAR-T) in hematologic malignancies. It relies on the pool of functional T cells to retain the developmental potential to serially kill targeted cells. However, failure in the continuous supply and persistence of functional T cells has been recognized as a critical barrier to sustainable responses. Conferring stemness on infused T cells, yielding stem cell-like memory T cells (TSCM) characterized by constant self-renewal and multilineage differentiation similar to pluripotent stem cells, is indeed necessary and promising for enhancing T cell function and sustaining antitumor immunity. Therefore, it is crucial to identify TSCM cell induction regulators and acquire more TSCM cells as resource cells during production and after infusion to improve antitumoral efficacy. Recently, four common cytokine receptor γ chain (γc) family cytokines, encompassing interleukin-2 (IL-2), IL-7, IL-15, and IL-21, have been widely used in the development of long-lived adoptively transferred TSCM in vitro. However, challenges, including their non-specific toxicities and off-target effects, have led to substantial efforts for the development of engineered versions to unleash their full potential in the induction and maintenance of T cell stemness in ACT. In this review, we summarize the roles of the four γc family cytokines in the orchestration of adoptively transferred T cell stemness, introduce their engineered versions that modulate TSCM cell formation and demonstrate the potential of their various combinations. Video Abstract.
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Affiliation(s)
- Mengshi Luo
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjian Gong
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuewen Zhang
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huayi Li
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ding Ma
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qinglei Gao
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yong Fang
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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24
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Mimic S, Aru B, Pehlivanoğlu C, Sleiman H, Andjus PR, Yanıkkaya Demirel G. Immunology of amyotrophic lateral sclerosis - role of the innate and adaptive immunity. Front Neurosci 2023; 17:1277399. [PMID: 38105925 PMCID: PMC10723830 DOI: 10.3389/fnins.2023.1277399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 11/07/2023] [Indexed: 12/19/2023] Open
Abstract
This review aims to summarize the latest evidence about the role of innate and adaptive immunity in Amyotrophic Lateral Sclerosis (ALS). ALS is a devastating neurodegenerative disease affecting upper and lower motor neurons, which involves essential cells of the immune system that play a basic role in innate or adaptive immunity, that can be neurotoxic or neuroprotective for neurons. However, distinguishing between the sole neurotoxic or neuroprotective function of certain cells such as astrocytes can be challenging due to intricate nature of these cells, the complexity of the microenvironment and the contextual factors. In this review, in regard to innate immunity we focus on the involvement of monocytes/macrophages, microglia, the complement, NK cells, neutrophils, mast cells, and astrocytes, while regarding adaptive immunity, in addition to humoral immunity the most important features and roles of T and B cells are highlighted, specifically different subsets of CD4+ as well as CD8+ T cells. The role of autoantibodies and cytokines is also discussed in distinct sections of this review.
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Affiliation(s)
- Stefan Mimic
- Centre for Laser Microscopy, Institute of Physiology and Biochemistry “Jean Giaja”, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Başak Aru
- Immunology Department, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Cemil Pehlivanoğlu
- Immunology Department, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Hadi Sleiman
- Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Pavle R. Andjus
- Centre for Laser Microscopy, Institute of Physiology and Biochemistry “Jean Giaja”, Faculty of Biology, University of Belgrade, Belgrade, Serbia
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Massironi S, Mulinacci G, Gallo C, Elvevi A, Danese S, Invernizzi P, Vespa E. Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms. Cells 2023; 12:2473. [PMID: 37887317 PMCID: PMC10605530 DOI: 10.3390/cells12202473] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophilic infiltration of the esophagus. It arises from a complex interplay of genetic predisposition (susceptibility loci), environmental triggers (allergens and dietary antigens), and a dysregulated immune response, mainly mediated by type 2 T helper cell (Th2)-released cytokines, such as interleukin (IL)-4, IL-5, and IL-13. These cytokines control eosinophil recruitment and activation as well as tissue remodeling, contributing to the characteristic features of EoE. The pathogenesis of EoE includes epithelial barrier dysfunction, mast cell activation, eosinophil degranulation, and fibrosis. Epithelial barrier dysfunction allows allergen penetration and promotes immune cell infiltration, thereby perpetuating the inflammatory response. Mast cells release proinflammatory mediators and promote eosinophil recruitment and the release of cytotoxic proteins and cytokines, causing tissue damage and remodeling. Prolonged inflammation can lead to fibrosis, resulting in long-term complications such as strictures and dysmotility. Current treatment options for EoE are limited and mainly focus on dietary changes, proton-pump inhibitors, and topical corticosteroids. Novel therapies targeting key inflammatory pathways, such as monoclonal antibodies against IL-4, IL-5, and IL-13, are emerging in clinical trials. A deeper understanding of the complex pathogenetic mechanisms behind EoE will contribute to the development of more effective and personalized therapeutic strategies.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Giacomo Mulinacci
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Camilla Gallo
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Edoardo Vespa
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy
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26
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Brammer JE, Ballen K, Sokol L, Querfeld C, Nakamura R, Mishra A, McLaughlin EM, Feith D, Azimi N, Waldmann TA, Tagaya Y, Loughran T. Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia. Blood 2023; 142:1271-1280. [PMID: 37352612 PMCID: PMC10613725 DOI: 10.1182/blood.2022017643] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/25/2023] Open
Abstract
T-cell large granular lymphocytic leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes that can result in severe neutropenia, anemia, and bone marrow failure. Strong evidence from patients and mouse models demonstrate the critical role of interleukin-15 (IL-15) in T-LGLL pathogenesis. BNZ-1 is a pegylated peptide that selectively inhibits the binding of IL-15 and other γc cytokines to their cellular receptor complex, which has demonstrated efficacy in ex vivo T-LGLL cells and transgenic mice in preclinical studies. We conducted a phase 1/2 trial of BNZ-1 in patients with T-LGLL who had hematocytopenias (anemia or neutropenia) and required therapy. Clinical responses were assessed using hematologic parameters (improvement in hematocytopenias) based on response criteria from the Eastern Cooperative Oncology Group 5998 T-LGLL trial. BNZ-1 demonstrated clinical partial responses in 20% of patients with T-LGLL with minimal toxicity and the maximum tolerated dose was not reached. Furthermore, T-LGL leukemic cells showed significantly increased apoptosis in response to BNZ-1 treatment as early as day 2, including in clinical nonresponders, with changes that remained statistically different from baseline throughout treatment (P < .005). We report first-in-human proof that T-LGL leukemic cells are dependent on IL-15 and that intervention with IL-15 inhibition with BNZ-1 in patients with T-LGLL shows therapeutic effects, which carries important implications for the understanding of the pathogenesis of this disease. This trial was registered at www.clinicaltrials.gov as #NCT03239392.
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Affiliation(s)
- Jonathan E. Brammer
- Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH
| | - Karen Ballen
- Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA
| | - Lubomir Sokol
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa Bay, FL
| | | | | | - Anjali Mishra
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology and Department of Cancer Biology, Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
| | - Eric M. McLaughlin
- Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH
| | - David Feith
- Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA
| | | | - Thomas A. Waldmann
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Yutaka Tagaya
- Institute for Human Virology, University of Maryland, Baltimore, MD
| | - Thomas Loughran
- Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA
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27
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Ravalet N, Guermouche H, Hirsch P, Picou F, Foucault A, Gallay N, Martignoles JA, Beaud J, Suner L, Deswarte C, Lachot S, Rault E, Largeaud L, Gissot V, Béné MC, Gyan E, Delhommeau F, Herault O. Modulation of bone marrow and peripheral blood cytokine levels by age and clonal hematopoiesis in healthy individuals. Clin Immunol 2023; 255:109730. [PMID: 37562724 DOI: 10.1016/j.clim.2023.109730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 07/10/2023] [Accepted: 07/20/2023] [Indexed: 08/12/2023]
Abstract
Aging is associated with bone marrow (BM) inflammaging and, in some individuals, with the onset of clonal hematopoiesis (CH) of indeterminate potential. In this study conducted on 94 strictly healthy volunteers (18 to 80 yo), we measured BM and peripheral blood (PB) plasma levels of 49 hematopoietic and inflammatory cytokines. With aging, 7 cytokines increased in BM (FLT3L, CXCL9, HGF, FGF-2, CCL27, IL-16, IL-18) and 8 decreased (G-CSF, TNF, IL-2, IL-15, IL-17A, CCL7, IL-4, IL-10). In PB, 10 cytokines increased with age (CXCL9, FLT3L, CCL27, CXCL10, HGF, CCL11, IL-16, IL-6, IL-1 beta, CCL2). CH was associated with higher BM levels of MIF and IL-1 beta, lower BM levels of IL-9 and IL-5 and higher PB levels of IL-15, VEGF-A, IL-2, CXCL8, CXCL1 and G-CSF. These reference values provide a useful tool to investigate anomalies related to inflammaging and potentially leading to the onset of age-related myeloid malignancies or inflammatory conditions.
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Affiliation(s)
- Noémie Ravalet
- CNRS EMR 7001 LNOx "Leukemic niche and redox metabolism", EA7501 GICC, Tours, France; Tours University Hospital, Department of Biological Hematology, Tours, France
| | - Hélène Guermouche
- Sorbonne University, INSERM, Saint-Antoine Research Center, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Pierre Hirsch
- Sorbonne University, INSERM, Saint-Antoine Research Center, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Frédéric Picou
- CNRS EMR 7001 LNOx "Leukemic niche and redox metabolism", EA7501 GICC, Tours, France; Tours University Hospital, Department of Biological Hematology, Tours, France
| | - Amélie Foucault
- CNRS EMR 7001 LNOx "Leukemic niche and redox metabolism", EA7501 GICC, Tours, France; Tours University Hospital, Department of Biological Hematology, Tours, France
| | - Nathalie Gallay
- CNRS EMR 7001 LNOx "Leukemic niche and redox metabolism", EA7501 GICC, Tours, France; Tours University Hospital, Department of Biological Hematology, Tours, France
| | - Jean-Alain Martignoles
- Sorbonne University, INSERM, Saint-Antoine Research Center, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Jenny Beaud
- Sorbonne University, INSERM, Saint-Antoine Research Center, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Ludovic Suner
- Sorbonne University, INSERM, Saint-Antoine Research Center, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Caroline Deswarte
- Sorbonne University, INSERM, Saint-Antoine Research Center, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Sébastien Lachot
- Tours University Hospital, Department of Biological Hematology, Tours, France
| | - Emmanuelle Rault
- Tours University Hospital, Department of Biological Hematology, Tours, France
| | - Laëtitia Largeaud
- Sorbonne University, INSERM, Saint-Antoine Research Center, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Valérie Gissot
- INSERM CIC 1415, Tours University Hospital, Tours, France
| | - Marie-Christine Béné
- Nantes University Hospital, Hematology Biology and INSERM CRCI2NA, Nantes, France; FHU GOAL "Grand Ouest Against Leukemia", Angers, France
| | - Emmanuel Gyan
- CNRS EMR 7001 LNOx "Leukemic niche and redox metabolism", EA7501 GICC, Tours, France; Tours University Hospital, Department of Hematology and Cell Therapy, Tours, France
| | - François Delhommeau
- Sorbonne University, INSERM, Saint-Antoine Research Center, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France; OPALE Carnot Institute, Paris, France; CNRS GDR3697 Micronit "Microenvironment of tumor niches", Tours, France.
| | - Olivier Herault
- CNRS EMR 7001 LNOx "Leukemic niche and redox metabolism", EA7501 GICC, Tours, France; Tours University Hospital, Department of Biological Hematology, Tours, France; FHU GOAL "Grand Ouest Against Leukemia", Angers, France; OPALE Carnot Institute, Paris, France; CNRS GDR3697 Micronit "Microenvironment of tumor niches", Tours, France.
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28
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Howard JN, Bosque A. IL-15 and N-803 for HIV Cure Approaches. Viruses 2023; 15:1912. [PMID: 37766318 PMCID: PMC10537516 DOI: 10.3390/v15091912] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
In spite of the advances in antiretroviral therapy to treat HIV infection, the presence of a latent reservoir of HIV-infected cells represents the largest barrier towards finding a cure. Among the different strategies being pursued to eliminate or reduce this latent reservoir, the γc-cytokine IL-15 or its superagonist N-803 are currently under clinical investigation, either alone or with other interventions. They have been shown to reactivate latent HIV and enhance immune effector function, both of which are potentially required for effective reduction of latent reservoirs. In here, we present a comprehensive literature review of the different in vitro, ex vivo, and in vivo studies conducted to date that are aimed at targeting HIV reservoirs using IL-15 and N-803.
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Affiliation(s)
| | - Alberto Bosque
- Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037, USA;
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29
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Dickerson LK, Carter JA, Kohli K, Pillarisetty VG. Emerging interleukin targets in the tumour microenvironment: implications for the treatment of gastrointestinal tumours. Gut 2023; 72:1592-1606. [PMID: 37258094 DOI: 10.1136/gutjnl-2023-329650] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/15/2023] [Indexed: 06/02/2023]
Abstract
The effectiveness of antitumour immunity is dependent on intricate cytokine networks. Interleukins (ILs) are important mediators of complex interactions within the tumour microenvironment, including regulation of tumour-infiltrating lymphocyte proliferation, differentiation, migration and activation. Our evolving and increasingly nuanced understanding of the cell type-specific and heterogeneous effects of IL signalling has presented unique opportunities to fine-tune elaborate IL networks and engineer new targeted immunotherapeutics. In this review, we provide a primer for clinicians on the challenges and potential of IL-based treatment. We specifically detail the roles of IL-2, IL-10, IL-12 and IL-15 in shaping the tumour-immune landscape of gastrointestinal malignancies, paying particular attention to promising preclinical findings, early-stage clinical research and innovative therapeutic approaches that may properly place ILs to the forefront of immunotherapy regimens.
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Affiliation(s)
| | - Jason A Carter
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
| | - Karan Kohli
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
- Flatiron Bio, Palo Alto, California, USA
| | - Venu G Pillarisetty
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
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30
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Böhme R, Daniel C, Ferrazzi F, Angeloni M, Ekici AB, Winkler TH, Hilgers KF, Wellmann U, Voll RE, Amann K. Cardiovascular changes in the NZB/W F1 mouse model of lupus nephritis. Front Cardiovasc Med 2023; 10:1182193. [PMID: 37554366 PMCID: PMC10405627 DOI: 10.3389/fcvm.2023.1182193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 07/04/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Patients with systemic lupus erythematosus (SLE), an autoimmune disease, have a higher risk of cardiovascular (CV) disease and death. In addition, up to 40%-50% of SLE patients develop lupus nephritis (LN) and chronic kidney disease, which is an additional CV risk factor. Thus, the individual contributions of LN and other SLE-specific factors to CV events are unclear. METHODS In this study, we investigated the effect of LN on the development of CV changes using the female NZBxNZW F1 (NZB/W) mouse model of lupus-like disease, with female NZW mice as controls. Standard serologic, morphologic, immunohistologic, and molecular analyses were performed. In a separate group of NZB/W mice, systolic blood pressure (BP) was measured during the course of the disease using tail plethysmography. RESULTS Our data show marked CV changes in NZB/W mice, i.e., increased heart weight, hypertrophy of the left ventricle (LV) and septum, and increased wall thickness of the intramyocardial arteries and the aorta, which correlated with the progression of renal damage, but not with the age of the mice. In addition, systolic BP was increased in NZB/W mice only when kidney damage progressed and proteinuria was present. Pathway analysis based on gene expression data revealed a significant upregulation of the response to interferon beta in NZB/W mice with moderate kidney injury compared with NZB mice. Furthermore, IFI202b and IL-6 mRNA expression is correlated with CV changes. Multiple linear regression analysis demonstrated serum urea as a surrogate marker of kidney function and IFI202b expression as an independent predictor for LV wall thickness. In addition, deposition of complement factors CFD and C3c in hearts from NZB/W mice was seen, which correlated with the severity of kidney disease. CONCLUSIONS Thus, we postulate that the pathogenesis of CV disease in SLE is affected by renal impairment, i.e., LN, but it can also be partly influenced by lupus-specific cardiac expression of pro-inflammatory factors and complement deposition.
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Affiliation(s)
- Romy Böhme
- Department of Nephropathology, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
| | - Christoph Daniel
- Department of Nephropathology, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
| | - Fulvia Ferrazzi
- Department of Nephropathology, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
- Institute of Pathology, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
| | - Miriam Angeloni
- Institute of Pathology, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
| | - Arif Bülent Ekici
- Institute of Human Genetics, University Hospital Erlangen, Friedrich–Alexander–Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Thomas H. Winkler
- Divison of Genetics, Department of Biology, Nikolaus–Fiebiger–Center of Molecular Medicine, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
| | - Karl-Friedrich Hilgers
- Department of Nephrology and Hypertension, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
| | - Ute Wellmann
- Divison of Genetics, Department of Biology, Nikolaus–Fiebiger–Center of Molecular Medicine, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
| | - Reinhard E. Voll
- Department of Rheumatology and Clinical Immunology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Kerstin Amann
- Department of Nephropathology, Friedrich–Alexander–Universität (FAU) Erlangen–Nürnberg, Erlangen, Germany
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Cai M, Huang X, Huang X, Ju D, Zhu YZ, Ye L. Research progress of interleukin-15 in cancer immunotherapy. Front Pharmacol 2023; 14:1184703. [PMID: 37251333 PMCID: PMC10213988 DOI: 10.3389/fphar.2023.1184703] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 05/04/2023] [Indexed: 05/31/2023] Open
Abstract
Interleukin-15 (IL-15) is a cytokine that belongs to the interleukin-2 (IL-2) family and is essential for the development, proliferation, and activation of immune cells, including natural killer (NK) cells, T cells and B cells. Recent studies have revealed that interleukin-15 also plays a critical role in cancer immunotherapy. Interleukin-15 agonist molecules have shown that interleukin-15 agonists are effective in inhibiting tumor growth and preventing metastasis, and some are undergoing clinical trials. In this review, we will summarize the recent progress in interleukin-15 research over the past 5 years, highlighting its potential applications in cancer immunotherapy and the progress of interleukin-15 agonist development.
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Affiliation(s)
- Menghan Cai
- School of Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Xuan Huang
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Xiting Huang
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Dianwen Ju
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Yi Zhun Zhu
- School of Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Li Ye
- School of Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
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Ichinohe D, Muroya T, Akasaka H, Hakamada K. Skeletal muscle mass and quality before preoperative chemotherapy influence postoperative long-term outcomes in esophageal squamous cell carcinoma patients. World J Gastrointest Surg 2023; 15:621-633. [PMID: 37206067 PMCID: PMC10190735 DOI: 10.4240/wjgs.v15.i4.621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/08/2023] [Accepted: 03/23/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Previous reports have focused on muscle mass as a prognostic factor in esophageal cancer.
AIM To investigate how preoperative body type influences the prognosis of patients with esophageal squamous cell carcinoma who underwent neoadjuvant chemotherapy (NAC) and surgery.
METHODS The subjects were 131 patients with clinical stage II/III esophageal squamous cell carcinoma who underwent subtotal esophagectomy after NAC. Skeletal muscle mass and quality were calculated based on computed tomography images prior to NAC, and their statistical association with long-term outcomes was examined retrospectively in this case-control study.
RESULTS The disease-free survival rates in the low psoas muscle mass index (PMI) group vs the high PMI group were 41.3% vs 58.8% (P = 0.036), respectively. In the high intramuscular adipose tissue content (IMAC) group vs the low IMAC group, the disease-free survival rates were 28.5% vs 57.6% (P = 0.021), respectively. The overall survival (OS) rates for the low PMI group vs the high PMI group were 41.3% vs 64.5% (P = 0.008), respectively, and for the high IMAC group vs the low IMAC group, they were 29.9% vs 61.9% (P = 0.024), respectively. Analysis of the OS rate revealed significant differences in patients aged 60 years or older (P = 0.018), those with pT3 or above disease (P = 0.021), or those with lymph node metastasis (P = 0.006), aside from PMI and IMAC. Multivariate analysis demonstrated that pT3 or above [hazard ratio (HR): 1.966, 95% confidence interval (CI): 1.089-3.550, P = 0.025), lymph node metastasis (HR: 2.154, 95%CI: 1.118-4.148, P = 0.022), low PMI (HR: 2.266, 95%CI: 1.282-4.006, P = 0.005), and high IMAC (HR: 2.089, 95%CI: 1.036-4.214, P = 0.022) were significant prognostic factors for esophageal squamous cell carcinoma.
CONCLUSION Skeletal muscle mass and quality before NAC in patients with esophageal squamous cell carcinoma are significant prognostic factors for postoperative OS.
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Affiliation(s)
- Daichi Ichinohe
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 0368562, Aomori, Japan
| | - Takahiro Muroya
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 0368562, Aomori, Japan
| | - Harue Akasaka
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 0368562, Aomori, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 0368562, Aomori, Japan
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Wang Y, Chen H, Zhao M, Feng L, Liu Z, Zeng Q, Shi W, Zhu W, Song L, Zhu J, Lu H. Oxidation and reduction analysis of therapeutic recombinant human interleukin-15 by HPLC and LC-MS. Appl Microbiol Biotechnol 2023; 107:3217-3227. [PMID: 37058229 DOI: 10.1007/s00253-023-12508-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/26/2023] [Accepted: 03/29/2023] [Indexed: 04/15/2023]
Abstract
Being an important immune stimulant of T lymphocytes and NK cells, the recombinant human interleukin-15 (rhIL-15) has been extensively researched in tumor immunotherapy or as a vaccine adjuvant. However, the rhIL-15 manufacturing level lags far behind its growing clinical demand due to the lack of efficient and exact analysis methodologies to characterize the trace by-products, typically redox and deamidation. In order to improve the production and quality control of rhIL-15, here we developed an expanded resolution reverse-phase high-performance liquid chromatography (ExRP-HPLC) approach to quickly and accurately analyze the oxidation and reduction by-products of rhIL-15, which may appear during the purification processes. Firstly, we developed RP-HPLC methods which can separate rhIL-15 fractions with different levels of oxidization or reduction, respectively, and the redox status of each peak was then determined by measuring the intact mass with a high-resolution mass spectrometer (UPLC-MS). To further clarify the complex pattern of oxidization of specific residues, the peaks with various oxidation levels were digested into pieces for peptide mapping to pinpoint the exact changes of oxygen and hydrogen atoms in the rhIL-15 by-products. In addition, we performed the ExRP-HPLC and UPLC-MS analysis of partially deamidated rhIL-15 to characterize their oxidation and reduction. Our work is the first in-depth characterization of the redox by-products of rhIL-15, even for deamidated impurities. The ExRP-HPLC method we reported can facilitate the rapid and accurate quality analysis of rhIL-15, which is substantially helpful for streamlining the industrial manufacturing of rhIL-15 to better meet the demands of clinical applications. KEYPOINTS: • The oxidization and reduction rhIL-15 by-products were characterized for the first time. • The changes of oxygen and hydrogen atoms in rhIL-15 redox by-products were accurately determined by UPLC-MS. • Oxidation and reduction by-products of deamidated rhIL-15 were further analyzed.
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Affiliation(s)
- Yang Wang
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Huanhuan Chen
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Meiqi Zhao
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Lei Feng
- Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China
| | - Zexin Liu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Qiongya Zeng
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Wenqiang Shi
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Wen Zhu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Luyao Song
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Jianwei Zhu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
| | - Huili Lu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
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Badeński A, Badeńska M, Świętochowska E, Janek A, Gliwińska A, Morawiec-Knysak A, Szczepańska M. Assessment of Interleukin-15 (IL-15) Concentration in Children with Idiopathic Nephrotic Syndrome. Int J Mol Sci 2023; 24:ijms24086993. [PMID: 37108157 PMCID: PMC10139059 DOI: 10.3390/ijms24086993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/06/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Idiopathic nephrotic syndrome (INS) is a chronic glomerular disease in children, characterized by severe proteinuria, hypoalbuminemia, and/or presence of edema and hyperlipidemia. The pathogenesis, however, has not been yet established. The clinical course of the disease is characterized by frequent relapses. Interleukin-15 (IL-15) is a pro-inflammatory cytokine, that apart from its involvement in the immune system, was found to be playing a vital role in various cells' functioning, including renal tissue. It is desirable to look for new predictors of INS. Our study aimed to evaluate IL-15 as a potential marker in the early diagnosis of the disease. The cohort participating in the study consisted of patients hospitalized in Clinical Hospital No. 1 in Zabrze, from December 2019 to December 2021, including study group with INS (n = 30) and control group (n = 44). Results: The concentration of IL-15 in both serum and urine was significantly elevated in patients with INS, compared to healthy controls. The cytokine might serve as a marker of the disease, however, further research on larger study groups is needed.
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Affiliation(s)
- Andrzej Badeński
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland
| | - Marta Badeńska
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. Jordana 19, 41-808 Zabrze-Rokitnica, Poland
| | - Artur Janek
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland
| | - Aleksandra Gliwińska
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland
| | - Aurelia Morawiec-Knysak
- Department of Pediatric Nephrology with Dialysis Division for Children, Public Clinical Hospital No. 1 in Zabrze, ul. 3 Maja 13/15, 41-800 Zabrze, Poland
| | - Maria Szczepańska
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13/15, 41-800 Zabrze, Poland
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Zhang Y, Su J. Interleukin-2 family cytokines: An overview of genes, expression, signaling and functional roles in teleost. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 141:104645. [PMID: 36696924 DOI: 10.1016/j.dci.2023.104645] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 01/11/2023] [Accepted: 01/20/2023] [Indexed: 06/17/2023]
Abstract
The interleukin-2 (IL-2) family cytokines include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, which share γ chain (γc) subunit in receptors. The IL-2 family cytokines have unique biological effects that regulate differentiation, survival and activation of multiple lymphocyte lineages. Deficiency of IL-2 family signaling pathway in mammals prevents CD4+ T cells from developing effector functions and CD8+ T cells from developing immunological memory. In the present review, we addressed available information from teleost IL-2 family cytokines and discussed implications in teleost immunity. Also, we described and discussed their expression profiles, receptors, signaling transductions and functions. In teleost, IL-2 family has 5 members (IL-2, IL-4/13, IL-7, IL-15, IL-21) without IL-9, and their receptors share a common γc subunit and include other 6 subunits (IL-2Rβ1/2, IL-4Rα1/2, IL-13Rα1/2, IL-7Rα, IL-15Rα, and IL-21Rα1/2). Some paralogues have changes in domain structure and show differential expression, modulation, functions. IL-2 family cytokines constitutively express in many immune associated tissues and are largely induced after pathogenic microbial stimulation. In general, there are relatively conserved functions in the IL-2 family throughout vertebrates, and many of the key IL-2 family members are important in lymphocyte proliferation and differentiation, development, inflammation from fishes to mammals. This review will give an update on the effective information of teleost IL-2 family cytokines. Thus, it will provide a source of reference for other researchers/readers and inspire further interest.
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Affiliation(s)
- Yanqi Zhang
- College of Fisheries, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, 430070, China; Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, China
| | - Jianguo Su
- College of Fisheries, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, 430070, China; Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
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36
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Lee J, Robinson ME, Sun R, Kume K, Ma N, Cosgun KN, Chan LN, Leveille E, Geng H, Vykunta VS, Shy BR, Marson A, Katz S, Chen J, Paietta E, Meffre E, Vaidehi N, Müschen M. Dynamic phosphatase-recruitment controls B-cell selection and oncogenic signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.13.532151. [PMID: 36993276 PMCID: PMC10054997 DOI: 10.1101/2023.03.13.532151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Initiation of B-cell receptor (BCR) 1 signaling, and subsequent antigen-encounter in germinal centers 2,3 represent milestones of B-lymphocyte development that are both marked by sharp increases of CD25 surface-expression. Oncogenic signaling in B-cell leukemia (B-ALL) 4 and lymphoma 5 also induced CD25-surface expression. While CD25 is known as an IL2-receptor chain on T- and NK-cells 6-9 , the significance of its expression on B-cells was unclear. Our experiments based on genetic mouse models and engineered patient-derived xenografts revealed that, rather than functioning as an IL2-receptor chain, CD25 expressed on B-cells assembled an inhibitory complex including PKCδ and SHIP1 and SHP1 phosphatases for feedback control of BCR-signaling or its oncogenic mimics. Recapitulating phenotypes of genetic ablation of PKCδ 10 - 12 , SHIP1 13,14 and SHP1 14, 15,16 , conditional CD25-deletion decimated early B-cell subsets but expanded mature B-cell populations and induced autoimmunity. In B-cell malignancies arising from early (B-ALL) and late (lymphoma) stages of B-cell development, CD25-loss induced cell death in the former and accelerated proliferation in the latter. Clinical outcome annotations mirrored opposite effects of CD25-deletion: high CD25 expression levels predicted poor clinical outcomes for patients with B-ALL, in contrast to favorable outcomes for lymphoma-patients. Biochemical and interactome studies revealed a critical role of CD25 in BCR-feedback regulation: BCR-signaling induced PKCδ-mediated phosphorylation of CD25 on its cytoplasmic tail (S 268 ). Genetic rescue experiments identified CD25-S 268 tail-phosphorylation as central structural requirement to recruit SHIP1 and SHP1 phosphatases to curb BCR-signaling. A single point mutation CD25 S268A abolished recruitment and activation of SHIP1 and SHP1 to limit duration and strength of BCR-signaling. Loss of phosphatase-function, autonomous BCR-signaling and Ca 2+ -oscillations induced anergy and negative selection during early B-cell development, as opposed to excessive proliferation and autoantibody production in mature B-cells. These findings highlight the previously unrecognized role of CD25 in assembling inhibitory phosphatases to control oncogenic signaling in B-cell malignancies and negative selection to prevent autoimmune disease.
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37
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Abeynaike SA, Huynh TR, Mehmood A, Kim T, Frank K, Gao K, Zalfa C, Gandarilla A, Shultz L, Paust S. Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection. Viruses 2023; 15:365. [PMID: 36851579 PMCID: PMC9960100 DOI: 10.3390/v15020365] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/18/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.
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Affiliation(s)
- Shawn A. Abeynaike
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Tridu R. Huynh
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Scripps Research Translational Institute, La Jolla, CA 92037, USA
- Division of Internal Medicine, Scripps Clinic/Scripps Green Hospital, La Jolla, CA 92037, USA
| | - Abeera Mehmood
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Teha Kim
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Kayla Frank
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Kefei Gao
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Cristina Zalfa
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Angel Gandarilla
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | | | - Silke Paust
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Sindaco P, Pandey H, Isabelle C, Chakravarti N, Brammer JE, Porcu P, Mishra A. The role of interleukin-15 in the development and treatment of hematological malignancies. Front Immunol 2023; 14:1141208. [PMID: 37153603 PMCID: PMC10157481 DOI: 10.3389/fimmu.2023.1141208] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/22/2023] [Indexed: 05/09/2023] Open
Abstract
Cytokines are a vital component of the immune system that controls the activation and growth of blood cells. However, chronic overexpression of cytokines can trigger cellular events leading to malignant transformation. The cytokine interleukin-15 (IL-15) is of particular interest, which has been shown to contribute to the development and progression of various hematological malignancies. This review will provide an overview of the impact of the immunopathogenic function of IL-15 by studying its role in cell survival, proliferation, inflammation, and treatment resistance. We will also review therapeutic approaches for inhibiting IL-15 in blood cancers.
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Affiliation(s)
- Paola Sindaco
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Hritisha Pandey
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Colleen Isabelle
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Nitin Chakravarti
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United States
| | | | - Pierluigi Porcu
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Anjali Mishra
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United States
- Department of Pharmacology, Physiology and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, United States
- *Correspondence: Anjali Mishra,
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Mortier E, Maillasson M, Quéméner A. Counteracting Interleukin-15 to Elucidate Its Modes of Action in Physiology and Pathology. J Interferon Cytokine Res 2023; 43:2-22. [PMID: 36651845 DOI: 10.1089/jir.2022.0198] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Interleukin (IL)-15 belongs to the common gamma-dependent cytokine family, along with IL-2, IL-4, IL-7, IL-9, and IL-21. IL-15 is crucial for the homeostasis of Natural Killer (NK) and memory CD8 T cells, and to fight against cancer progression. However, dysregulations of IL-15 expression could occur and participate in the emergence of autoimmune inflammatory diseases as well as hematological malignancies. It is therefore important to understand the different modes of action of IL-15 to decrease its harmful action in pathology without affecting its beneficial effects in the immune system. In this review, we present the different approaches used by researchers to inhibit the action of IL-15, from most broad to the most selective. Indeed, it appears that it is important to selectively target the mode of action of the cytokine rather than the cytokine itself as they are involved in numerous biological processes.
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Affiliation(s)
- Erwan Mortier
- Nantes Université, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Mike Maillasson
- Nantes Université, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Agnès Quéméner
- Nantes Université, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
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40
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Ahsan M, Garneau L, Aguer C. The bidirectional relationship between AMPK pathway activation and myokine secretion in skeletal muscle: How it affects energy metabolism. Front Physiol 2022; 13:1040809. [PMID: 36479347 PMCID: PMC9721351 DOI: 10.3389/fphys.2022.1040809] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/04/2022] [Indexed: 11/12/2023] Open
Abstract
Myokines are peptides and proteins secreted by skeletal muscle cells, into the interstitium, or in the blood. Their regulation may be dependent or independent of muscle contraction to induce a variety of metabolic effects. Numerous myokines have been implicated in influencing energy metabolism via AMP-activated protein kinase (AMPK) signalling. As AMPK is centrally involved in glucose and lipid metabolism, it is important to understand how myokines influence its signalling, and vice versa. Such insight will better elucidate the mechanism of metabolic regulation during exercise and at rest. This review encompasses the latest research conducted on the relationship between AMPK signalling and myokines within skeletal muscles via autocrine or paracrine signalling.
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Affiliation(s)
- Mahdi Ahsan
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Léa Garneau
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Institut du Savoir Montfort –Recherche, Ottawa, ON, Canada
| | - Céline Aguer
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Institut du Savoir Montfort –Recherche, Ottawa, ON, Canada
- Department of Physiology, Faculty of Medicine and Health Sciences, McGill University—Campus Outaouais, Gatineau, QC, Canada
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada
- Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada
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41
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Luo Z, He Z, Qin H, Chen Y, Qi B, Lin J, Sun Y, Sun J, Su X, Long Z, Chen S. Exercise-induced IL-15 acted as a positive prognostic implication and tumor-suppressed role in pan-cancer. Front Pharmacol 2022; 13:1053137. [PMID: 36467072 PMCID: PMC9712805 DOI: 10.3389/fphar.2022.1053137] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 11/07/2022] [Indexed: 09/12/2023] Open
Abstract
Objective: Exercise can produce a large number of cytokines that may benefit cancer patients, including Interleukin 15 (IL-15). IL-15 is a cytokine that has multiple functions in regulating the adaptive and innate immune systems and tumorigenesis of lung and breast cancers. However, the roles of IL-15 in other types of cancer remain unknown. In this article, we try to systematically analyze if IL-15 is a potential molecular biomarker for predicting patient prognosis in pan-cancer and its connection with anti-cancer effects of exercise. Methods: The expression of IL-15 was detected by The Cancer Genome Atlas (TCGA) database, Human protein Atlas (HPA), and Genotype Tissue-Expression (GTEX) database. Analysis of IL-15 genomic alterations and protein expression in human organic tissues was analyzed by the cBioPortal database and HPA. The correlations between IL-15 expression and survival outcomes, clinical features, immune-associated cell infiltration, and ferroptosis/cuproptosis were analyzed using the TCGA, ESTIMATE algorithm, and TIMER databases. Gene Set Enrichment Analysis (GSEA) was performed to evaluate the biological functions of IL-15 in pan-cancer. Results: The differential analysis suggested that the level of IL-15 mRNA expression was significantly downregulated in 12 tumor types compared with normal tissues, which is similar to the protein expression in most cancer types. The high expression of IL-15 could predict the positive survival outcome of patients with LUAD (lung adenocarcinoma), COAD (colon adenocarcinoma), COADREAD (colon and rectum adenocarcinoma), ESCA (esophageal carcinoma), SKCM (skin cutaneous melanoma), UCS (uterine carcinosarcoma), and READ (rectum adenocarcinoma). Moreover, amplification was found to be the most frequent mutation type of IL-15 genomic. Furthermore, the expression of IL-15 was correlated to the infiltration levels of various immune-associated cells in pan-cancer assessed by the ESTIMATE algorithm and TIMER database. In addition, IL-15 is positively correlated with ferroptosis/cuproptosis-related genes (ACSL4 and LIPT1) in pan-cancer. Levels of IL-15 were reported to be elevated in humans for 10-120 min following an acute exercise. Therefore, we hypothesized that the better prognosis of pan-cancer patients with regular exercise may be achieved by regulating level of IL-15. Conclusion: Our results demonstrated that IL-15 is a potential molecular biomarker for predicting patient prognosis, immunoreaction, and ferroptosis/cuproptosis in pan-cancer and partly explained the anti-cancer effects of exercise.
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Affiliation(s)
- Zhiwen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhong He
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai, China
| | - Haocheng Qin
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai, China
| | - Yisheng Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Beijie Qi
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University, Shanghai, China
| | - Jinrong Lin
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yaying Sun
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Junming Sun
- Laboratory Animal Center, Guangxi Medical University, Nanning, China
| | - Xiaoping Su
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, College & Hospital of Stomatology, Guangxi Medical University, Nanning, China
| | - Ziwen Long
- Department of Gastric Cancer Sugery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shiyi Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
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Waldemer-Streyer RJ, Kim D, Chen J. Muscle cell-derived cytokines in skeletal muscle regeneration. FEBS J 2022; 289:6463-6483. [PMID: 35073461 PMCID: PMC9308828 DOI: 10.1111/febs.16372] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 12/14/2022]
Abstract
Regeneration of the mammalian adult skeletal muscle is a well-orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major class of regulators of skeletal myogenesis. It is well established that infiltrating immune cells at the site of muscle injury secrete cytokines, which play critical roles in the myofibre repair and regeneration process. In the past 10-15 years, skeletal muscle itself has emerged as a prolific producer of cytokines. Much attention in the field has been focused on the endocrine effects of muscle-secreted cytokines (myokines) on metabolic regulation. However, ample evidence suggests that muscle-derived cytokines also regulate myogenic differentiation and muscle regeneration in an autocrine manner. In this review, we survey cytokines that meet two criteria: (a) evidence of expression by muscle cells; (b) evidence demonstrating a myogenic function. Dozens of cytokines representing several major classes make up this group, and together they regulate all steps of the myogenic process. How such a large array of cytokines coordinate their signalling to form a regulatory network is a fascinating, pressing question. Functional studies that can distinguish the source of the cytokines in vivo are also much needed in order to facilitate exploration of their full therapeutic potential.
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Affiliation(s)
| | | | - Jie Chen
- Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave., Urbana, IL 61801
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Ma S, Caligiuri MA, Yu J. Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Trends Immunol 2022; 43:833-847. [PMID: 36058806 PMCID: PMC9612852 DOI: 10.1016/j.it.2022.08.004] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 10/14/2022]
Abstract
Natural killer (NK) cells, a crucial component of the innate immune system, have long been of clinical interest for their antitumor properties. Almost every aspect of NK cell immunity is regulated by interleukin-15 (IL-15), a cytokine in the common γ-chain family. Several current clinical trials are using IL-15 or its analogs to treat various cancers. Moreover, NK cells are being genetically modified to produce membrane-bound or secretory IL-15. Here, we discuss the key role of IL-15 signaling in NK cell immunity and provide an up-to-date overview of IL-15 in NK cell therapy.
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Affiliation(s)
- Shoubao Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA.
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA; Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Los Angeles, CA 91010, USA.
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Choi YJ, Lee H, Kim JH, Kim SY, Koh JY, Sa M, Park SH, Shin EC. CD5 Suppresses IL-15–Induced Proliferation of Human Memory CD8+ T Cells by Inhibiting mTOR Pathways. THE JOURNAL OF IMMUNOLOGY 2022; 209:1108-1117. [DOI: 10.4049/jimmunol.2100854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 07/20/2022] [Indexed: 01/04/2023]
Abstract
Abstract
IL-15 induces the proliferation of memory CD8+ T cells as well as NK cells. The expression of CD5 inversely correlates with the IL-15 responsiveness of human memory CD8+ T cells. However, whether CD5 directly regulates IL-15–induced proliferation of human memory CD8+ T cells is unknown. In the current study, we demonstrate that human memory CD8+ T cells in advanced stages of differentiation respond to IL-15 better than human memory CD8+ T cells in stages of less differentiation. We also found that the expression level of CD5 is the best correlate for IL-15 hyporesponsiveness among human memory CD8+ T cells. Importantly, we found that IL-15–induced proliferation of human memory CD8+ T cells is significantly enhanced by blocking CD5 with Abs or knocking down CD5 expression using small interfering RNA, indicating that CD5 directly suppresses the IL-15–induced proliferation of human memory CD8+ T cells. We also found that CD5 inhibits activation of the mTOR pathway, which is required for IL-15–induced proliferation of human memory CD8+ T cells. Taken together, the results indicate that CD5 is not just a correlative marker for IL-15 hyporesponsiveness, but it also directly suppresses IL-15–induced proliferation of human memory CD8+ T cells by inhibiting mTOR pathways.
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Affiliation(s)
- Young Joon Choi
- *Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
- †Department of Ophthalmology, Ajou University School of Medicine, Suwon, Korea
| | - Hoyoung Lee
- *Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
- ‡The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science, Daejeon, Republic of Korea; and
| | - Jong Hoon Kim
- *Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
- §Department of Dermatology, Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - So-Young Kim
- *Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - June-Young Koh
- *Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Moa Sa
- *Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Su-Hyung Park
- *Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Eui-Cheol Shin
- *Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
- ‡The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science, Daejeon, Republic of Korea; and
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45
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Interleukin 15 in Cell-Based Cancer Immunotherapy. Int J Mol Sci 2022; 23:ijms23137311. [PMID: 35806311 PMCID: PMC9266896 DOI: 10.3390/ijms23137311] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/24/2022] [Accepted: 06/25/2022] [Indexed: 02/01/2023] Open
Abstract
Cell-based cancer immunotherapy, such as chimeric antigen receptor (CAR) engineered T and natural killer (NK) cell therapies, has become a revolutionary new pillar in cancer treatment. Interleukin 15 (IL-15), a potent immunostimulatory cytokine that potentiates T and NK cell immune responses, has demonstrated the reliability and potency to potentially improve the therapeutic efficacy of current cell therapy. Structurally similar to interleukin 2 (IL-2), IL-15 supports the persistence of CD8+ memory T cells while inhibiting IL-2-induced T cell death that better maintains long-term anti-tumor immunity. In this review, we describe the biology of IL-15, studies on administrating IL-15 and/or its derivatives as immunotherapeutic agents, and IL-15-armored immune cells in adoptive cell therapy. We also discuss the advantages and challenges of incorporating IL-15 in cell-based immunotherapy and provide directions for future investigation.
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Delgado‐Dolset MI, Obeso D, Rodríguez‐Coira J, Tarin C, Tan G, Cumplido JA, Cabrera A, Angulo S, Barbas C, Sokolowska M, Barber D, Carrillo T, Villaseñor A, Escribese MM. Understanding uncontrolled severe allergic asthma by integration of omic and clinical data. Allergy 2022; 77:1772-1785. [PMID: 34839541 DOI: 10.1111/all.15192] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 10/04/2021] [Accepted: 11/02/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Asthma is a complex, multifactorial disease often linked with sensitization to house dust mites (HDM). There is a subset of patients that does not respond to available treatments, who present a higher number of exacerbations and a worse quality of life. To understand the mechanisms of poor asthma control and disease severity, we aim to elucidate the metabolic and immunologic routes underlying this specific phenotype and the associated clinical features. METHODS Eighty-seven patients with a clinical history of asthma were recruited and stratified in 4 groups according to their response to treatment: corticosteroid-controlled (ICS), immunotherapy-controlled (IT), biologicals-controlled (BIO) or uncontrolled (UC). Serum samples were analysed by metabolomics and proteomics; and classifiers were built using machine-learning algorithms. RESULTS Metabolomic analysis showed that ICS and UC groups cluster separately from one another and display the highest number of significantly different metabolites among all comparisons. Metabolite identification and pathway enrichment analysis highlighted increased levels of lysophospholipids related to inflammatory pathways in the UC patients. Likewise, 8 proteins were either upregulated (CCL13, ARG1, IL15 and TNFRSF12A) or downregulated (sCD4, CCL19 and IFNγ) in UC patients compared to ICS, suggesting a significant activation of T cells in these patients. Finally, the machine-learning model built including metabolomic and clinical data was able to classify the patients with an 87.5% accuracy. CONCLUSIONS UC patients display a unique fingerprint characterized by inflammatory-related metabolites and proteins, suggesting a pro-inflammatory environment. Moreover, the integration of clinical and experimental data led to a deeper understanding of the mechanisms underlying UC phenotype.
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Affiliation(s)
- María Isabel Delgado‐Dolset
- Institute of Applied Molecular Medicine (IMMA) Department of Basic Medical Sciences Facultad de Medicina Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO) Department of Chemistry and Biochemistry Facultad de Farmacia Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
| | - David Obeso
- Institute of Applied Molecular Medicine (IMMA) Department of Basic Medical Sciences Facultad de Medicina Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO) Department of Chemistry and Biochemistry Facultad de Farmacia Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
| | - Juan Rodríguez‐Coira
- Institute of Applied Molecular Medicine (IMMA) Department of Basic Medical Sciences Facultad de Medicina Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO) Department of Chemistry and Biochemistry Facultad de Farmacia Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
- Swiss Institute of Allergy and Asthma Research (SIAF) University of Zurich Zurich Switzerland
| | - Carlos Tarin
- Institute of Applied Molecular Medicine (IMMA) Department of Basic Medical Sciences Facultad de Medicina Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
| | - Ge Tan
- Swiss Institute of Allergy and Asthma Research (SIAF) University of Zurich Zurich Switzerland
| | - José A. Cumplido
- Hospital Universitario de Gran Canaria Doctor Negrin Las Palmas de Gran Canaria Spain
| | - Ana Cabrera
- Hospital Universitario de Gran Canaria Doctor Negrin Las Palmas de Gran Canaria Spain
| | - Santiago Angulo
- Department of Applied Mathematics and Statistics Universidad San Pablo‐CEU CEU Universities Madrid Spain
| | - Coral Barbas
- Centre for Metabolomics and Bioanalysis (CEMBIO) Department of Chemistry and Biochemistry Facultad de Farmacia Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
| | - Milena Sokolowska
- Swiss Institute of Allergy and Asthma Research (SIAF) University of Zurich Zurich Switzerland
| | - Domingo Barber
- Institute of Applied Molecular Medicine (IMMA) Department of Basic Medical Sciences Facultad de Medicina Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
| | - Teresa Carrillo
- Hospital Universitario de Gran Canaria Doctor Negrin Las Palmas de Gran Canaria Spain
| | - Alma Villaseñor
- Institute of Applied Molecular Medicine (IMMA) Department of Basic Medical Sciences Facultad de Medicina Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
| | - María M. Escribese
- Institute of Applied Molecular Medicine (IMMA) Department of Basic Medical Sciences Facultad de Medicina Universidad San Pablo CEU CEU Universities Urbanización Montepríncipe Madrid Spain
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Gene Engineering T Cells with T-Cell Receptor for Adoptive Therapy. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2453:209-229. [PMID: 35622329 DOI: 10.1007/978-1-0716-2115-8_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Prior to clinical testing of adoptive T-cell therapy with T-cell receptor (TCR)-engineered T cells, TCRs need to be retrieved, annotated, gene-transferred, and extensively tested in vitro to accurately assess specificity and sensitivity of target recognition. Here, we present a fundamental series of protocols that cover critical preclinical parameters, thereby enabling the selection of candidate TCRs for clinical testing.
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48
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Meghnem D, Maillasson M, Barbieux I, Morisseau S, Keita D, Jacques Y, Quéméner A, Mortier E. Selective Targeting of IL-15Rα Is Sufficient to Reduce Inflammation. Front Immunol 2022; 13:886213. [PMID: 35592318 PMCID: PMC9110858 DOI: 10.3389/fimmu.2022.886213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/05/2022] [Indexed: 11/21/2022] Open
Abstract
Cytokines are crucial molecules for maintaining the proper functioning of the immune system. Nevertheless, a dysregulation of cytokine expression could be involved in the pathogenesis of autoimmune diseases. Interleukin (IL)-15 is a key factor for natural killer cells (NK) and CD8 T cells homeostasis, necessary to fight cancer and infections but could also be considered as a pro-inflammatory cytokine involved in autoimmune inflammatory disease, including rheumatoid arthritis, psoriasis, along with tumor necrosis factor alpha (TNF-α), IL-6, and IL-1β. The molecular mechanisms by which IL-15 exerts its inflammatory function in these diseases are still unclear. In this study, we generated an IL-15-derived molecule called NANTIL-15 (New ANTagonist of IL-15), designed to selectively inhibit the action of IL-15 through the high-affinity trimeric IL-15Rα/IL-2Rβ/γc receptor while leaving IL-15 signaling through the dimeric IL-2Rβ/γc receptor unaffected. Administrating of NANTIL-15 in healthy mice did not affect the IL-15-dependent cell populations such as NK and CD8 T cells. In contrast, we found that NANTIL-15 efficiently reduced signs of inflammation in a collagen-induced arthritis model. These observations demonstrate that the inflammatory properties of IL-15 are linked to its action through the trimeric IL-15Rα/IL-2Rβ/γc receptor, highlighting the interest of selectively targeting this receptor.
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Affiliation(s)
- Dihia Meghnem
- Nantes University, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Mike Maillasson
- Nantes University, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France.,Nantes University, Centre Hospitalo-Universitaire (CHU) Nantes, Inserm, CNRS, SFR Bonamy, UMS BioCore, IMPACT Platform, Nantes, France
| | - Isabelle Barbieux
- Nantes University, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Sébastien Morisseau
- Nantes University, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France.,Centre Hospitalo-Universitaire (CHU), Nantes Hospital, Nantes, France
| | - Dalloba Keita
- Nantes University, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Yannick Jacques
- Nantes University, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Agnès Quéméner
- Nantes University, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Erwan Mortier
- Nantes University, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France.,Nantes University, Centre Hospitalo-Universitaire (CHU) Nantes, Inserm, CNRS, SFR Bonamy, UMS BioCore, IMPACT Platform, Nantes, France
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Advances of research of Fc-fusion protein that activate NK cells for tumor immunotherapy. Int Immunopharmacol 2022; 109:108783. [PMID: 35561479 DOI: 10.1016/j.intimp.2022.108783] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/02/2022] [Accepted: 04/14/2022] [Indexed: 12/21/2022]
Abstract
The rapid development of bioengineering technology has introduced Fc-fusion proteins, representing a novel kind of recombinant protein, as promising biopharmaceutical products in tumor therapy. Numerous related anti-tumor Fc-fusion proteins have been investigated and are in different stages of development. Fc-fusion proteins are constructed by fusing the Fc-region of the antibody with functional proteins or peptides. They retain the bioactivity of the latter and partial properties of the former. This structural and functional advantage makes Fc-fusion proteins an effective tool in tumor immunotherapy, especially for the recruitment and activation of natural killer (NK) cells, which play a critical role in tumor immunotherapy. Even though tumor cells have developed mechanisms to circumvent the cytotoxic effect of NK cells or induce defective NK cells, Fc-fusion proteins have been proven to effectively activate NK cells to kill tumor cells in different ways, such as antibody-dependent cell-mediated cytotoxicity (ADCC), activate NK cells in different ways in order to promote killing of tumor cells. In this review, we focus on NK cell-based immunity for cancers and current research progress of the Fc-fusion proteins for anti-tumor therapy by activating NK cells.
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50
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Interleukin-15 augments NK cell-mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies. Blood Adv 2022; 7:384-394. [PMID: 35475910 PMCID: PMC9898617 DOI: 10.1182/bloodadvances.2021006440] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 02/23/2022] [Accepted: 03/18/2022] [Indexed: 02/01/2023] Open
Abstract
Interleukin-15 (IL-15) monotherapy substantially increases the number and activity of natural killer (NK) cells and CD8+ T cells but has not produced clinical responses. In a xenograft mouse model, IL-15 enhanced the NK cell-mediated antibody-dependent cell cytotoxicity (ADCC) of the anti-CD52 antibody alemtuzumab and led to significantly more durable responses than alemtuzumab alone. To evaluate whether IL-15 potentiates ADCC in humans, we conducted a phase 1 single-center study of recombinant human IL-15 and alemtuzumab in patients with CD52-positive mature T-cell malignances. We gave IL-15 subcutaneously 5 days per week for 2 weeks in a 3 + 3 dose escalation scheme (at 0.5, 1, and 2 μg/kg), followed by standard 3 times weekly alemtuzumab IV for 4 weeks. There were no dose-limiting toxicities or severe adverse events attributable to IL-15 in the 11 patients treated. The most common adverse events were lymphopenia (100%), alemtuzumab-related infusion reactions (90%), anemia (90%), and neutropenia (72%). There were 3 partial and 2 complete responses, with an overall response rate of 45% and median duration of response 6 months. Immediately after 10 days of IL-15, there was a median 7.2-fold increase in NK cells and 2.5-fold increase in circulating CD8+ T cells, whereas the number of circulating leukemic cells decreased by a median 38% across all dose levels. Treatment with IL-15 was associated with increased expression of NKp46 and NKG2D, markers of NK-cell activation, and increased ex vivo ADCC activity of NK cells, whereas inhibitory receptors PD1 and Tim3 were decreased. This trial was registered at www.clinicaltrials.gov as #NCT02689453.
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