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1
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Masmoudi D, Villalba M, Alix-Panabières C. Natural killer cells: the immune frontline against circulating tumor cells. J Exp Clin Cancer Res 2025; 44:118. [PMID: 40211394 PMCID: PMC11983744 DOI: 10.1186/s13046-025-03375-x] [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: 01/10/2025] [Accepted: 03/25/2025] [Indexed: 04/14/2025] Open
Abstract
Natural killer (NK) play a key role in controlling tumor dissemination by mediating cytotoxicity towards cancer cells without the need of education. These cells are pivotal in eliminating circulating tumor cells (CTCs) from the bloodstream, thus limiting cancer spread and metastasis. However, aggressive CTCs can evade NK cell surveillance, facilitating tumor growth at distant sites. In this review, we first discuss the biology of NK cells, focusing on their functions within the tumor microenvironment (TME), the lymphatic system, and circulation. We then examine the immune evasion mechanisms employed by cancer cells to inhibit NK cell activity, including the upregulation of inhibitory receptors. Finally, we explore the clinical implications of monitoring circulating biomarkers, such as NK cells and CTCs, for therapeutic decision-making and emphasize the need to enhance NK cell-based therapies by overcoming immune escape mechanisms.
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Affiliation(s)
- Doryan Masmoudi
- Laboratory of Rare Circulating Human Cells, University Medical Center of Montpellier, Montpellier, France
| | - Martin Villalba
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Catherine Alix-Panabières
- Laboratory of Rare Circulating Human Cells, University Medical Center of Montpellier, Montpellier, France.
- CREEC/CANECEV, MIVEGEC (CREES), University of Montpellier, CNRS, Montpellier, IRD, France.
- European Liquid Biopsy Society (ELBS), Hamburg, Germany.
- LCCRH, Site Unique de Biologie (SUB), 641, Avenue du Doyen Gaston Giraud, Montpellier, 34093, France.
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2
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Teramoto K, Ueda Y, Murai R, Ogasawara K, Nakayama M, Ishigaki H, Itoh Y. A hemoperfusion column selectively adsorbs LAP+ lymphocytes to improve anti-tumor immunity and survival of tumor-bearing rats. PLoS One 2025; 20:e0305153. [PMID: 40053558 PMCID: PMC11888139 DOI: 10.1371/journal.pone.0305153] [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: 05/25/2024] [Accepted: 12/19/2024] [Indexed: 03/09/2025] Open
Abstract
Reducing the number of immunosuppressive cells in blood is a potential strategy for activating anti-tumor immunity, which provides a promising approach to cancer treatment. In this study, we developed an adsorbent designed to selectively target and adsorb lymphocytes expressing latency-associated peptide (LAP), which is abundantly expressed on the surface of CD4+ regulatory T cells (Tregs) and CD14+ monocytes. We investigated whether diethylenetriamine-conjugated polysulfone adsorbent-based direct hemoperfusion (DHP) enhances anti-tumor immunity in a rat cancer model with KDH-V liver cells. Our findings revealed that DHP significantly reduced LAP+ Tregs in both peripheral blood and tumor tissues in treated mice. Consequently, cytotoxic T-lymphocytes increased in tumor-bearing rats. The anti-tumor effect was negated by the addition of cells detached from the absorbent, indicating that these cells play a crucial role in inhibiting the observed therapeutic effect. The results suggest that depleting LAP+ immunosuppressive cells in blood can enhance anti-tumor immunity and improve survival of patients.
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Affiliation(s)
- Kazuo Teramoto
- Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Yuji Ueda
- Osaka General Hospital of West Japan Railway Company, Osaka, Japan
| | - Ryosuke Murai
- Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
- Department of Urology, Shiga University of Medical Science, Otsu, Japan
| | - Kazumasa Ogasawara
- Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Misako Nakayama
- Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Hirohito Ishigaki
- Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Yasushi Itoh
- Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
- Central Research Laboratory, Shiga University of Medical Science, Otsu, Japan
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3
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Singer M, Elsayed AM, Husseiny MI. Regulatory T-cells: The Face-off of the Immune Balance. FRONT BIOSCI-LANDMRK 2024; 29:377. [PMID: 39614434 DOI: 10.31083/j.fbl2911377] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/29/2024] [Accepted: 08/13/2024] [Indexed: 12/01/2024]
Abstract
Regulatory T-cells (Tregs) play a crucial role in maintaining immune homeostasis, ensuring a balanced immune response. Tregs primarily operate in an antigen-specific fashion, facilitated by their distinct distribution within discrete niches. Tregs have been studied extensively, from their point of origin in the thymus origin to their fate in the periphery or organs. Signals received from antigen-presenting cells (APCs) stimulate Tregs to dampen inflammation. Almost all tumors are characterized by a pathological abundance of immune suppression in their microenvironment. Conversely, the lack thereof proves detrimental to immunological disorders. Achieving a balanced expression of Tregs in relation to other immune compartments is important in establishing an effective and adaptable immune tolerance towards cancer cells and autoantigens. In the context of cancer, it is essential to decrease the frequency of Tregs to overcome tumor suppression. A lower survival rate is associated with the presence of excessive exhausted effector immune cells and an increased frequency of regulatory cells. However, when it comes to treating graft rejection and autoimmune diseases, the focus lies on immune tolerance and the transfer of Tregs. Here, we explore the complex mechanisms that Tregs use in human disease to balance effector immune cells.
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Affiliation(s)
- Mahmoud Singer
- School of Medicine, University of California Irvine, Irvine, CA 92617, USA
| | - Ahmed M Elsayed
- Division of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Mohamed I Husseiny
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
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4
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Zhang J, Guan X, Zhong X. Immunosenescence in digestive system cancers: Mechanisms, research advances, and therapeutic strategies. Semin Cancer Biol 2024; 106-107:234-250. [PMID: 39510149 DOI: 10.1016/j.semcancer.2024.10.006] [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: 08/13/2024] [Revised: 10/21/2024] [Accepted: 10/30/2024] [Indexed: 11/15/2024]
Abstract
Increasing lifespans and external environmental factors have contributed to the increase of age-related diseases, particularly cancer. A decrease in immune surveillance and clearance of cancer cells is the result of immunosenescence, which involves the remodeling of immune organs, the changes and functional decline of immune cell subsets, in association with systemic low-grade chronic inflammation. Stem cells aging in bone marrow and thymic involution are the most important causes of immunosenescence. Senescent cancer cells promote the differentiation, recruitment, and functional upregulation of immune-suppressive cell subsets e.g. regulatory T cells (Tregs), myeloid-derived suppressor cell (MDSC), tumor-associated macrophages (TAMS) through senescence-associated secretory phenotype (SASP) further exacerbating the immunosuppressive microenvironment. For digestive system cancers, age-related damage to the intestinal mucosal barrier, the aging of gut-associated lymphoid tissue (GALT), exposure to xenobiotic stimuli throughout life, and dysbiosis make the local immune microenvironment more vulnerable. This article systematically reviews the research progress of immunosenescence and immune microenvironment in digestive system cancers, as well as the exploration of related therapy strategies, hoping to point out new directions for research in the digestive system cancers.
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Affiliation(s)
- Junyan Zhang
- Department of Surgical Oncology and General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China
| | - Xiaojiao Guan
- Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, China.
| | - Xinwen Zhong
- Department of Thoracic Surgery, First Affiliated Hospital, China Medical University, Shenyang, China.
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5
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Gootjes C, Zwaginga JJ, Roep BO, Nikolic T. Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function. Cells 2024; 13:941. [PMID: 38891073 PMCID: PMC11172350 DOI: 10.3390/cells13110941] [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: 02/28/2024] [Revised: 04/18/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Regulatory T cells (Tregs) are essential to maintain immune homeostasis by promoting self-tolerance. Reduced Treg numbers or functionality can lead to a loss of tolerance, increasing the risk of developing autoimmune diseases. An overwhelming variety of human Tregs has been described, based on either specific phenotype, tissue compartment, or pathological condition, yet the bulk of the literature only addresses CD25-positive and CD127-negative cells, coined by naturally occurring Tregs (nTregs), most of which express the transcription factor Forkhead box protein 3 (FOXP3). While the discovery of FOXP3 was seminal to understanding the origin and biology of nTregs, there is evidence in humans that not all T cells expressing FOXP3 are regulatory, and that not all Tregs express FOXP3. Namely, the activation of human T cells induces the transient expression of FOXP3, irrespective of whether they are regulatory or inflammatory effectors, while some induced T cells that may be broadly defined as Tregs (e.g., Tr1 cells) typically lack demethylation and do not express FOXP3. Furthermore, it is unknown whether and how many nTregs exist without FOXP3 expression. Several other candidate regulatory molecules, such as GITR, Lag-3, GARP, GPA33, Helios, and Neuropilin, have been identified but subsequently discarded as Treg-specific markers. Multiparametric analyses have uncovered a plethora of Treg phenotypes, and neither single markers nor combinations thereof can define all and only Tregs. To date, only the functional capacity to inhibit immune responses defines a Treg and distinguishes Tregs from inflammatory T cells (Teffs) in humans. This review revisits current knowledge of the Treg universe with respect to their heterogeneity in phenotype and function. We propose that it is unavoidable to characterize human Tregs by their phenotype in combination with their function, since phenotype alone does not unambiguously define Tregs. There is an unmet need to align the expression of specific markers or combinations thereof with a particular suppressive function to coin functional Treg entities and categorize Treg diversity.
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Affiliation(s)
- Chelsea Gootjes
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (J.J.Z.); (T.N.)
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6
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Wang J, Wang S, Zhang Y, Zhang W. Bibliometric analysis of evolutionary trajectory and prospective directions of LAG-3 in cancer. Front Immunol 2024; 15:1329775. [PMID: 38390331 PMCID: PMC10881671 DOI: 10.3389/fimmu.2024.1329775] [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: 10/29/2023] [Accepted: 01/24/2024] [Indexed: 02/24/2024] Open
Abstract
Objectives Perform a bibliometric analysis on the role of LAG-3 in the domain of cancer, elucidate the prevailing areas of research, and visually depict the evolutionary trajectory and prospective directions of LAG-3 research over the past twenty-three decades. Materials and methods Between 2000 and 2023, a comprehensive review of scholarly articles pertaining to LAG-3 research in the context of cancer was carried out using the Web of Science Core Collection (WoSCC) database. Bibliometric analysis can be conducted by taking advantage of VOSviewer (version 1.6.16) and CiteSpace (version 6.2.R4). Create a network diagram to visually represent various authors, countries, and organizations while assessing the publishing years, journals, references, and keywords. Results In conclusion, 1841 records were identified and published in 587 publications. These records were authored by 12,849 individuals affiliated with 2491 institutes across 74 countries. There has been a substantial surge in publications subsequent to 2013. The USA, China, and Germany gave the majority of records, amounting to 69.69%. American institutions actively engage in collaboration with institutions located in other countries. Triebel, F., Vignali, Dario A. A., Workman, Creg J. Drake, Charles G., and Elkord, Eyad are highly regarded authors in their respective fields. However, it is worth noting that Triebel exhibits limited collaboration with other writers. The examination of the role of LAG-3 in cancer and its potential for use in clinical settings is a discernible trend, as seen by keyword analysis. Conclusion The scientific interest in and attention towards LAG-3 has experienced a significant rise since 2013. The United States is leading the way, with China following closely behind. Promoting collaboration among writers, nations, and institutions with varied backgrounds is imperative. The discipline of immunotherapy is currently seeing ongoing progress. A thorough investigation of the distinctive cis ligand TCR-CD3 complex of LAG-3 and its signal transduction mechanism is necessary. Additionally, it is worthwhile to explore novel combinations of LAG-3 therapy.
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Affiliation(s)
| | | | | | - Wei Zhang
- Department of Breast Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China
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7
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Milanović M, Bekić M, Đokić J, Vučević D, Čolić M, Tomić S. Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response. Int J Biol Sci 2024; 20:1064-1087. [PMID: 38322117 PMCID: PMC10845299 DOI: 10.7150/ijbs.91109] [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: 10/14/2023] [Accepted: 01/09/2024] [Indexed: 02/08/2024] Open
Abstract
Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to induce Th1 cells. However, αKG also promoted IL-1β secretion by mature moDCs, despite inflammasome downregulation, potentiating their Th17 polarizing capacity. αKG induced the expression of anti-oxidative enzymes and hypoxia-induced factor (HIF)-1α in moDCs, activated Akt/FoxO1 pathway and increased autophagy flux, oxidative phosphorylation (OXPHOS) and glycolysis. This correlated with a higher capacity of immature αKG-moDCs to induce Th2 cells, and conventional regulatory T cells in an indolamine-dioxygenase (IDO)-1-dependent manner. Additionally, αKG increased moDCs' capacity to induce non-conventional T regulatory (Tr)-1 and IL-10-producing CD8+T cells via up-regulated immunoglobulin-like transcript (ILT3) expression in OXPHOS-dependent manner. These results suggested that exogenous αKG-altered redox metabolism in moDCs contributed to their tolerogenic properties, which could be relevant for designing more efficient therapeutic approaches in DCs-mediated immunotherapies.
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Affiliation(s)
- Marijana Milanović
- Medical Faculty of the Military Medical Academy, University of Defense, Belgrade, Serbia
| | - Marina Bekić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
| | - Jelena Đokić
- Institute for Molecular Genetics and Genetical Engineering, University in Belgrade, Belgrade, Serbia
| | - Dragana Vučević
- Medical Faculty of the Military Medical Academy, University of Defense, Belgrade, Serbia
| | - Miodrag Čolić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
| | - Sergej Tomić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
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8
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Whiteside SK, Grant FM, Alvisi G, Clarke J, Tang L, Imianowski CJ, Zhang B, Evans AC, Wesolowski AJ, Conti AG, Yang J, Lauder SN, Clement M, Humphreys IR, Dooley J, Burton O, Liston A, Alloisio M, Voulaz E, Langhorne J, Okkenhaug K, Lugli E, Roychoudhuri R. Acquisition of suppressive function by conventional T cells limits antitumor immunity upon T reg depletion. Sci Immunol 2023; 8:eabo5558. [PMID: 38100544 PMCID: PMC7615475 DOI: 10.1126/sciimmunol.abo5558] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 01/15/2023] [Accepted: 11/10/2023] [Indexed: 12/17/2023]
Abstract
Regulatory T (Treg) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt Treg cell-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling Treg cell-targeted immunotherapy in mice, we find that CD4+ Foxp3- conventional T (Tconv) cells acquire suppressive function upon depletion of Foxp3+ Treg cells, limiting therapeutic efficacy. Foxp3- Tconv cells within tumors adopt a Treg cell-like transcriptional profile upon ablation of Treg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4+ Tconv cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon Treg cell depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, and mediate IL-10-dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon Treg cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg cell-targeted therapies.
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Affiliation(s)
- Sarah K Whiteside
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Francis M Grant
- Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge, Cambridgeshire CB22 3AT, UK
| | - Giorgia Alvisi
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - James Clarke
- La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Leqi Tang
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Charlotte J Imianowski
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Baojie Zhang
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Alexander C Evans
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Alexander J Wesolowski
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Alberto G Conti
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Jie Yang
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Sarah N Lauder
- Division of Infection and Immunity/System Immunity University Research Institute, Cardiff University, Cardiff CF14 4XN, UK
| | - Mathew Clement
- Division of Infection and Immunity/System Immunity University Research Institute, Cardiff University, Cardiff CF14 4XN, UK
| | - Ian R Humphreys
- Division of Infection and Immunity/System Immunity University Research Institute, Cardiff University, Cardiff CF14 4XN, UK
| | - James Dooley
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Oliver Burton
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Adrian Liston
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Marco Alloisio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy
- Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Emanuele Voulaz
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy
- Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Jean Langhorne
- Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Klaus Okkenhaug
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Enrico Lugli
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Rahul Roychoudhuri
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
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Yu J, Xu W, Dong Q, Ji Q, Cheng M, Hu D, Cai Y, Zeng Q, Yu K. Latency-associated peptide (LAP) +CD4 + regulatory T cells prevent atherosclerosis by modulating macrophage polarization. Clin Immunol 2023; 255:109767. [PMID: 37689092 DOI: 10.1016/j.clim.2023.109767] [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] [Received: 06/14/2023] [Revised: 09/03/2023] [Accepted: 09/05/2023] [Indexed: 09/11/2023]
Abstract
RATIONALE A persistent autoimmune and inflammatory response plays a critical role in the progression of atherosclerosis. The transcription factor forkhead box P3 (Foxp3)+CD4+ regulatory T cells (Foxp3+ Tregs) attenuate atherosclerosis. Latency-associated peptide (LAP)+CD4+ T cells are a new class of Tregs whose role in atherosclerosis is unknown. OBJECTIVE To investigate the function of CD4+LAP+ Tregs in inhibiting inflammation and preventing atherosclerosis. METHODS AND RESULTS Depletion of CD4+LAP+ Tregs results in aggravated inflammation and atherosclerotic lesions. Mechanistically, CD4+LAP+ Treg depletion was associated with decreased M2-like macrophages and increased Th1 and Th17 cells, characterized by increased unstable plaque promotion and decreased expression of inflammation-resolving factors in both arteries and immune organs. In contrast, adoptive transfer of CD4+LAP+ Tregs to ApoE-/- mice or CD4-/-ApoE-/- mice led to decreased atherosclerotic lesions. Compared with control animals, adoptive transfer of CD4+LAP+ Tregs induced M2-like macrophage differentiation within the atherosclerotic lesion and spleen, associated with increased collagen and α-SMA in plaques and decreased expression of MMP-2 and MMP-9. Mechanistic studies reveal that isolated CD4+LAP+ Tregs exhibit a tolerance phenotype, with increased expression of inhibitory cytokines and coinhibitory molecules. After coculture with CD4+LAP+ Tregs, monocytes/macrophages display typical features of M2 macrophages, including upregulated expression of CD206 and Arg-1 and decreased production of MCP-1, IL-6, IL-1β and TNF-α, which was almost abrogated by transwell and partially TGF-β1 neutralization. RNA-seq analysis showed different gene expression profiles between CD4+LAP+ Tregs and LAP-CD4+ T cells and between CD4+LAP+ Tregs of ApoE-/- mice and CD4+LAP+ Tregs of C57BL/6 mice, of which Fancd2 and IL4i1 may contribute to the powerful inhibitory properties of CD4+LAP+ Tregs. Furthermore, the number and the suppressive properties of CD4+LAP+ Tregs were impaired by oxLDL. CONCLUSIONS Our data indicate that the remaining CD4+LAP+ Tregs play a protective role in atherosclerosis by modulating monocyte/macrophage differentiation and regulatory factors, which may partly explain the protective effect of T cells tolerance in atherosclerosis. Moreover, adoptive transfer of CD4+LAP+ Tregs constitutes a novel approach to treat atherosclerosis.
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Affiliation(s)
- Jian Yu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Wenbin Xu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Qian Dong
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Qingwei Ji
- Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Min Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Desheng Hu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yifan Cai
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Qiutang Zeng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
| | - Kunwu Yu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
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10
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Aguinaga-Barrilero A, Juarez I, Vaquero-Yuste C, Molina-Alejandre M, Gutiérrez-Calvo A, Lasa I, López A, Gómez R, Molanes-López EM, Martin-Villa JM. Higher prevalence of LAP+ (Latency TGFβ-Associated Peptide) T cells at the tissue level in patients with early gastric cancer. Cell Immunol 2022; 382:104635. [PMID: 36332356 DOI: 10.1016/j.cellimm.2022.104635] [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: 03/31/2022] [Revised: 10/13/2022] [Accepted: 10/22/2022] [Indexed: 01/13/2023]
Abstract
The presence of cells with regulatory functions in patients with cancer is one of the mechanisms whereby the immune system cannot confront tumor growth. We sought to determine the prevalence of immunoregulatory T-cell subpopulations, expressing the latency TGFβ-associated peptide (LAP), in patients with gastric adenocarcinoma. T cells were enriched from blood or gastric tissue (tumoral, TT or tumor-free, TF) samples from 22 patients, 6 with early (EGC) and 16 with advanced gastric cancer (AGC). CD4, CD8, LAP, FoxP3 and IFN-γ were measured by cytometry. CD8 + LAP + cells were increased at tumoral sites, especially in early stages of the disease, as compared to tumor-free explants (EGC 5.28 % [4.67-6.64]*; AGC 2.90 % [1.37-4.44]; TF 3.14 % [2.33-4.16]; *p < 0.05 vs TF). Likewise, the LAP+/CD8 + LAP- ratio is increased in gastric samples from patients with early disease (EGC 0.38 [0.30-0.45]*, AGC 0.12 [0.07-0.14]; TF 0.12 [0.09-0.31]; *p < 0.05 vs AGC).Disease progression is accompanied by decreased LAP membrane expression and, probably, increased LAP secretion, therefore limiting the response to the tumor.
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Affiliation(s)
- Ana Aguinaga-Barrilero
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
| | - Ignacio Juarez
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
| | - Christian Vaquero-Yuste
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
| | - Marta Molina-Alejandre
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
| | - Alberto Gutiérrez-Calvo
- Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.
| | - Inmaculada Lasa
- Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.
| | - Adela López
- Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.
| | - Remedios Gómez
- Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.
| | - Elisa M Molanes-López
- Departamento de Estadística e Investigación Operativa, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - José M Martin-Villa
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
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11
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Talaat IM, Elemam NM, Zaher S, Saber-Ayad M. Checkpoint molecules on infiltrating immune cells in colorectal tumor microenvironment. Front Med (Lausanne) 2022; 9:955599. [PMID: 36072957 PMCID: PMC9441912 DOI: 10.3389/fmed.2022.955599] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 07/29/2022] [Indexed: 11/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancer types worldwide, with a high mortality rate due to metastasis. The tumor microenvironment (TME) contains multiple interactions between the tumor and the host, thus determining CRC initiation and progression. Various immune cells exist within the TME, such as tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs). The immunotherapy approach provides novel opportunities to treat solid tumors, especially toward immune checkpoints. Despite the advances in the immunotherapy of CRC, there are still obstacles to successful treatment. In this review, we highlighted the role of these immune cells in CRC, with a particular emphasis on immune checkpoint molecules involved in CRC pathogenesis.
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Affiliation(s)
- Iman M. Talaat
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Noha M. Elemam
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Shroque Zaher
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Maha Saber-Ayad
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt
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12
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Aristin Revilla S, Kranenburg O, Coffer PJ. Colorectal Cancer-Infiltrating Regulatory T Cells: Functional Heterogeneity, Metabolic Adaptation, and Therapeutic Targeting. Front Immunol 2022; 13:903564. [PMID: 35874729 PMCID: PMC9304750 DOI: 10.3389/fimmu.2022.903564] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/06/2022] [Indexed: 11/18/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low-dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches. Here, we review our understanding of the role of Treg cells in CRC, the possible mechanisms that support their homeostasis in the tumor microenvironment, and current approaches for manipulating Treg cells function in cancer.
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Affiliation(s)
- Sonia Aristin Revilla
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Onno Kranenburg
- Laboratory Translational Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Paul J. Coffer
- Center Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
- *Correspondence: Paul J. Coffer,
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13
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Zhong W, Fang C, Liu H, Zhang L, Zhang X, Zhong J, He X, Zhang L. LAP+CD4+T cells regulate the anti-tumor role of CIK cells in colorectal cancer through IL-10 and TGF-β. Am J Transl Res 2022; 14:3716-3728. [PMID: 35836905 PMCID: PMC9274552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 12/29/2021] [Indexed: 06/15/2023]
Abstract
The rate of colorectal cancer (CRC) is increasing. Adoptive immune cell therapy (ACT) is a research hotspot in CRC treatment, and the common adoptive cells are cytokine-induced killer cells (CIK). The problem of ACT is that some regulatory T cells (Treg) will affect the efficacy. Latent associated polypeptide (LAP)+CD4+T is a new Treg, and its immunosuppressive effect is much higher than that of traditional Tregs. This research mainly explored the influence of LAP+CD4+T cells on anti-tumor lethality of CIK cells, so as to fill this gap. The LAP+CD4+T CIK cells and LAP-CD4+T CIK cells were sorted by immunomagnetic beads. LAP+CD4+T cells were expanded in vitro, and high expression cytokine genes were screened by RT-qPCR. LAP+CD4+T and LAP-CD4+T CIK cells were co-cultured to test cyto-activity. Transplanted tumor models of CRC were established in nude mice, which were randomized into a control group (CG), CIK group, LAP (-) group, LAP (+) group, IL-10 siRNA group, and TGF-siRNA group, and the tumor growth in each group was observed. The research results revealed that interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) were highly expressed in LAP+CD4+T cells. LAP+CD4+T could effectively suppress CIK cell proliferation and activity. LAP-CD4+T could suppress IL-10 and TGF-β, and inhibit CIK cell apoptosis, proliferation, and tumor growth, thus improving their anti-tumor lethality. LAP+CD4+T cells regulate the anti-tumor role of CIK cells in CRC through IL-10 and TGF-β.
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Affiliation(s)
- Wu Zhong
- Department of Gastrointestinal Surgery, Ganzhou Hospital Affiliated to Nanchang UniversityGanzhou 341000, Jiangxi, China
| | - Chuanfa Fang
- Department of Gastrointestinal Surgery, Ganzhou Hospital Affiliated to Nanchang UniversityGanzhou 341000, Jiangxi, China
| | - Hongquan Liu
- Department of Gastrointestinal Surgery, Ganzhou Hospital Affiliated to Nanchang UniversityGanzhou 341000, Jiangxi, China
| | - Lei Zhang
- Department of Gastrointestinal Surgery, Ganzhou Hospital Affiliated to Nanchang UniversityGanzhou 341000, Jiangxi, China
| | - Xiaofei Zhang
- Department of Anorectal, Ganzhou Traditional Chinese Medicine HospitalGanzhou 341000, Jiangxi, China
| | - Junqiao Zhong
- Department of Gastrointestinal Surgery, Ganzhou Hospital Affiliated to Nanchang UniversityGanzhou 341000, Jiangxi, China
| | - Xianping He
- Department of Gastrointestinal Surgery, Ganzhou Hospital Affiliated to Nanchang UniversityGanzhou 341000, Jiangxi, China
| | - Leichang Zhang
- Department of Anorectal, Affiliated Hospital of Jiangxi University of Traditional Chinese MedicineNanchang 330006, Jiangxi, China
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Stachtea X, Loughrey MB, Salvucci M, Lindner AU, Cho S, McDonough E, Sood A, Graf J, Santamaria-Pang A, Corwin A, Laurent-Puig P, Dasgupta S, Shia J, Owens JR, Abate S, Van Schaeybroeck S, Lawler M, Prehn JHM, Ginty F, Longley DB. Stratification of chemotherapy-treated stage III colorectal cancer patients using multiplexed imaging and single-cell analysis of T-cell populations. Mod Pathol 2022; 35:564-576. [PMID: 34732839 PMCID: PMC8964416 DOI: 10.1038/s41379-021-00953-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 11/08/2022]
Abstract
Colorectal cancer (CRC) has one of the highest cancer incidences and mortality rates. In stage III, postoperative chemotherapy benefits <20% of patients, while more than 50% will develop distant metastases. Biomarkers for identification of patients at increased risk of disease recurrence following adjuvant chemotherapy are currently lacking. In this study, we assessed immune signatures in the tumor and tumor microenvironment (TME) using an in situ multiplexed immunofluorescence imaging and single-cell analysis technology (Cell DIVETM) and evaluated their correlations with patient outcomes. Tissue microarrays (TMAs) with up to three 1 mm diameter cores per patient were prepared from 117 stage III CRC patients treated with adjuvant fluoropyrimidine/oxaliplatin (FOLFOX) chemotherapy. Single sections underwent multiplexed immunofluorescence staining for immune cell markers (CD45, CD3, CD4, CD8, FOXP3, PD1) and tumor/cell segmentation markers (DAPI, pan-cytokeratin, AE1, NaKATPase, and S6). We used annotations and a probabilistic classification algorithm to build statistical models of immune cell types. Images were also qualitatively assessed independently by a Pathologist as 'high', 'moderate' or 'low', for stromal and total immune cell content. Excellent agreement was found between manual assessment and total automated scores (p < 0.0001). Moreover, compared to single markers, a multi-marker classification of regulatory T cells (Tregs: CD3+/CD4+FOXP3+/PD1-) was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.049 and 0.032) of FOLFOX-treated patients. Our results also showed that PD1- Tregs rather than PD1+ Tregs were associated with improved survival. These findings were supported by results from an independent FOLFOX-treated cohort of 191 stage III CRC patients, where higher PD1- Tregs were associated with an increase overall survival (p = 0.015) for CD3+/CD4+/FOXP3+/PD1-. Overall, compared to single markers, multi-marker classification provided more accurate quantitation of immune cell types with stronger correlations with outcomes.
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Affiliation(s)
- Xanthi Stachtea
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Maurice B Loughrey
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
- Department of Cellular Pathology, Royal Victoria Hospital, Belfast Health and Social Care trust, Belfast, UK
| | - Manuela Salvucci
- Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, 123 St. Stephen's Green, Dublin 2, Ireland
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Andreas U Lindner
- Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, 123 St. Stephen's Green, Dublin 2, Ireland
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Sanghee Cho
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | | | - Anup Sood
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - John Graf
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | | | - Alex Corwin
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | | | | | - Jinru Shia
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan R Owens
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Samantha Abate
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Sandra Van Schaeybroeck
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Mark Lawler
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, 123 St. Stephen's Green, Dublin 2, Ireland
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Fiona Ginty
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Daniel B Longley
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK.
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15
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Nayak SP, Bagchi B, Roy S. Effects of immunosuppressants on T-cell dynamics: Understanding from a generic coarse-grained immune network model. J Biosci 2022; 47:70. [PMID: 36503907 PMCID: PMC9734612 DOI: 10.1007/s12038-022-00312-4] [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] [Indexed: 12/14/2022]
Abstract
Long-term immunosuppressive therapy is a drug regimen often used to lower aggressive immune responses in various chronic inflammatory diseases. However, such long-term therapy leading to immune suppression may trigger other adverse reactions in the immune system. The rising concern regarding the optimal dose and duration of such treatment has motivated us to understand non-classical immunomodulatory responses induced by various immunosuppressive steroid and secosteroid drugs such as glucocorticoid and vitamin D supplements. The immunomodulatory actions of such immunosuppressants (that govern the adaptive immune response) are often mediated through their characteristic control over CD4+ T-cells involving pro- and antiinflammatory T-cells. Several early studies attempted to decode temporal and dose-dependent behaviors of such pro- and anti-inflammatory T-cells using the chemical dynamics approach. We first summarize these early works. Then, we develop a minimal coarse-grained kinetic network model to capture the commonality in their immunomodulatory functions. This generic model successfully reproduces the characteristic dynamical features, including the clinical latency period in long-term T-cell dynamics. The temporal behavior of T-cells is found to be sensitive to specific rate parameters and doses of immunosuppressants. The steady-state analysis reflects the transition from an early classified weakly regulated (autoimmune-prone) immune state to a strongly regulated state (immunocompromised state), separated by an intervening state of moderate/balanced regulation. An optimal dose and duration are essential in rescuing balanced immune regulation. This review elucidates how developing a simple generic coarse-grained immune network model may provide immense information that helps diagnose inefficacy in adaptive immune function before and after administering immunosuppressants such as glucocorticoid or vitamin D.
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Affiliation(s)
- Sonali Priyadarshini Nayak
- Department of Systems and Computational Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
- Max Planck School Matter to Life, University of Göttingen, Friedrich-Hund-Platz 1, 37077 Göttingen, Germany
| | - Biman Bagchi
- Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru, 560012 India
| | - Susmita Roy
- Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, 741246 India
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16
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Gabriely G, Ma D, Siddiqui S, Sun L, Skillin NP, Abou-El-Hassan H, Moreira TG, Donnelly D, da Cunha AP, Fujiwara M, Walton LR, Patel A, Krishnan R, Levine SS, Healy BC, Rezende RM, Murugaiyan G, Weiner HL. Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells. iScience 2021; 24:103347. [PMID: 34820606 PMCID: PMC8602030 DOI: 10.1016/j.isci.2021.103347] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 09/14/2021] [Accepted: 10/22/2021] [Indexed: 12/16/2022] Open
Abstract
Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-β on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.
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Affiliation(s)
- Galina Gabriely
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Jounce Therapeutics Inc, Cambridge, MA 02139, USA
| | - Duanduan Ma
- MIT Biomicro Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Shafiuddin Siddiqui
- Flow Cytometry Core Facility, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD 20892-4255, USA
| | - Linqing Sun
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL 60611, USA
| | - Nathaniel P. Skillin
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Chemical and Biological Engineering, The BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Hadi Abou-El-Hassan
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Thais G. Moreira
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Dustin Donnelly
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Andre P. da Cunha
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Jounce Therapeutics Inc, Cambridge, MA 02139, USA
| | - Mai Fujiwara
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Lena R. Walton
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Novartis Institute of BioMedical Research, Cambridge, MA 02139, USA
| | - Amee Patel
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Novartis Institute of BioMedical Research, Cambridge, MA 02139, USA
| | - Rajesh Krishnan
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Stuart S. Levine
- MIT Biomicro Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Brian C. Healy
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Rafael M. Rezende
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Gopal Murugaiyan
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Howard L. Weiner
- Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Szeponik L, Ahlmanner F, Sundström P, Rodin W, Gustavsson B, Bexe Lindskog E, Wettergren Y, Quiding-Järbrink M. Intratumoral regulatory T cells from colon cancer patients comprise several activated effector populations. BMC Immunol 2021; 22:58. [PMID: 34407765 PMCID: PMC8375143 DOI: 10.1186/s12865-021-00449-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022] Open
Abstract
Background Intratumoral regulatory T cells (Treg) in colon cancer are a heterogeneous cell population, with potential impact on patient outcome. Generally, a high Treg infiltration has been correlated to a worse patient outcome, but it is still unclear how the composition of different Treg subsets affects patient relapse and survival. In this study, we used mass and flow cytometry to characterize Treg in colon tumors and corresponding unaffected tissue, followed by a correlation to clinical parameters and patient outcome. Results Using mass cytometry, we defined 13 clusters of intestinal Treg, three of which were enriched in the tumors. The two most enriched clusters were defined by their expression of the proliferation marker Ki67 and CD56, respectively. The Treg accumulating in the tumors expressed inducible T-cell co-stimulator (ICOS), OX-40, and CD39, indicating that they were effector Treg (eTreg). Intratumoral CD39+ Treg also had a higher expression of Foxp3, suggesting a higher suppressive activity, and we subsequently used CD39 as a marker for eTreg. Our further studies showed that colon tumors can be divided into two tumor groups, based on the proportion of CD39+ putative eTreg in the tumors. This property was independent of both tumor microsatellite status and tumor stage, which are important factors in predicting cancer disease progression. In a prospective study of forty-four colon cancer patients, we also showed that patients with a high CD39 expression on tumor-infiltrating Treg have a tendency towards a less favorable patient outcome in terms of cumulative cancer-specific survival. Conclusions This study uncovers novel subsets of tumor-infiltrating Treg in colon cancer, and suggests that CD39 may be a potential therapeutic target in patients with microsatellite stable colon tumors, which are usually refractory to checkpoint blockade therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12865-021-00449-1.
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Affiliation(s)
- Louis Szeponik
- Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Box 435, 405 30, Göteborg, Sweden
| | - Filip Ahlmanner
- Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Box 435, 405 30, Göteborg, Sweden
| | - Patrik Sundström
- Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Box 435, 405 30, Göteborg, Sweden
| | - William Rodin
- Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Box 435, 405 30, Göteborg, Sweden
| | - Bengt Gustavsson
- Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Blå stråket 5, 413 45, Göteborg, Sweden
| | - Elinor Bexe Lindskog
- Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Blå stråket 5, 413 45, Göteborg, Sweden
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Blå stråket 5, 413 45, Göteborg, Sweden
| | - Marianne Quiding-Järbrink
- Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Box 435, 405 30, Göteborg, Sweden.
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18
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Lythgoe MP, Liu DSK, Annels NE, Krell J, Frampton AE. Gene of the month: lymphocyte-activation gene 3 (LAG-3). J Clin Pathol 2021; 74:543-547. [PMID: 34183437 DOI: 10.1136/jclinpath-2021-207517] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2021] [Indexed: 12/18/2022]
Abstract
Lymphocyte-activation gene 3 (LAG-3) is a coreceptor found on activated T-lymphocytes activated B-lymphocytes and natural killer (NK) cells. It is closely related to CD4 where it shares multiple common and divergent features. It contains specific binding sites with high affinity to major histocompatibility complex (MHC) Class II and functions as an inhibitor of T-cell signalling. Tumour-infiltrating lymphocytes with high LAG-3 expression have been found in many solid tumours including ovarian cancer, melanoma, colorectal cancer and haematological malignancies including Hodgkin and diffuse large B-cell lymphoma. LAG-3 antagonism has been demonstrated to restore the anti-tumourigenic function of T-cells in vivo, however, mechanistic knowledge remains relatively poorly defined. As other immune checkpoint inhibitors have transformed the management of difficult to treat cancers, such as melanoma, it is hoped that LAG-3 might have the same potential. This review will explore LAG-3 modulation as an anticancer therapy, highlighting recent clinical developments.
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Affiliation(s)
- Mark P Lythgoe
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Daniel Si Kit Liu
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Nicola E Annels
- Department of Clinical and Experimental Medicine, University of Surrey, Faculty of Health and Medical Sciences, Guildford, Surrey, UK
| | - Jonathan Krell
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Adam Enver Frampton
- Department of Surgery and Cancer, Imperial College London, London, UK .,Department of Clinical and Experimental Medicine, University of Surrey, Faculty of Health and Medical Sciences, Guildford, Surrey, UK.,HPB Surgical Unit, Royal Surrey NHS Foundation Trust, Guildford, UK
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19
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Nayak SP, Roy S. Immune phase transition under steroid treatment. Phys Rev E 2021; 103:062401. [PMID: 34271610 DOI: 10.1103/physreve.103.062401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 05/11/2021] [Indexed: 11/07/2022]
Abstract
The steroid hormone glucocorticoid (GC) is a well-known immunosuppressant that controls T-cell-mediated adaptive immune response. In this work, we have developed a minimal kinetic network model of T-cell regulation connecting relevant experimental and clinical studies to quantitatively understand the long-term effects of GC on pro-inflammatory T-cell (T_{pro}) and anti-inflammatory T-cell (T_{anti}) dynamics. Due to the antagonistic relation between these two types of T cells, their long-term steady-state population ratio helps us to characterize three classified immune regulations: (i) weak ([T_{pro}]>[T_{anti}]), (ii) strong ([T_{pro}]<[T_{anti}]), and (iii) moderate ([T_{pro}]∼[T_{anti}]), holding the characteristic bistability. In addition to the differences in their long-term steady-state outcome, each immune regulation shows distinct dynamical phases. In the presteady state, a characteristic intermediate stationary phase is observed to develop only in the moderate regulation regime. In the medicinal field, the resting time in this stationary phase is distinguished as a clinical latent period. GC dose-dependent steady-state analysis shows an optimal level of GC to drive a phase transition from the weak or autoimmune prone to the moderate regulation regime. Subsequently, the presteady state clinical latent period tends to diverge near that optimal GC level where [T_{pro}]:[T_{anti}] is highly balanced. The GC-optimized elongated stationary phase explains the rationale behind the requirement of long-term immune diagnostics, especially when long-term GC-based chemotherapeutics and other immunosuppressive drugs are administrated. Moreover, our study reveals GC sensitivity of clinical latent period, which might serve as an early warning signal in diagnosing different immune phases and determining immune phasewise steroid treatment.
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Affiliation(s)
| | - Susmita Roy
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Campus Road, Mohanpur, West Bengal 741246, India
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20
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Nussbaum YI, Manjunath Y, Suvilesh KN, Warren WC, Shyu CR, Kaifi JT, Ciorba MA, Mitchem JB. Current and Prospective Methods for Assessing Anti-Tumor Immunity in Colorectal Cancer. Int J Mol Sci 2021; 22:4802. [PMID: 33946558 PMCID: PMC8125332 DOI: 10.3390/ijms22094802] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) remains one of the deadliest malignancies worldwide despite recent progress in treatment strategies. Though immune checkpoint inhibition has proven effective for a number of other tumors, it offers benefits in only a small group of CRC patients with high microsatellite instability. In general, heterogenous cell groups in the tumor microenvironment are considered as the major barrier for unveiling the causes of low immune response. Therefore, deconvolution of cellular components in highly heterogeneous microenvironments is crucial for understanding the immune contexture of cancer. In this review, we assimilate current knowledge and recent studies examining anti-tumor immunity in CRC. We also discuss the utilization of novel immune contexture assessment methods that have not been used in CRC research to date.
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Affiliation(s)
- Yulia I. Nussbaum
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65201, USA; (Y.I.N.); (C.-R.S.); (J.T.K.)
| | - Yariswamy Manjunath
- Department of Surgery, Columbia, MO 65212, USA; (Y.M.); (K.N.S.); (W.C.W.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Kanve N. Suvilesh
- Department of Surgery, Columbia, MO 65212, USA; (Y.M.); (K.N.S.); (W.C.W.)
| | - Wesley C. Warren
- Department of Surgery, Columbia, MO 65212, USA; (Y.M.); (K.N.S.); (W.C.W.)
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
| | - Chi-Ren Shyu
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65201, USA; (Y.I.N.); (C.-R.S.); (J.T.K.)
| | - Jussuf T. Kaifi
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65201, USA; (Y.I.N.); (C.-R.S.); (J.T.K.)
- Department of Surgery, Columbia, MO 65212, USA; (Y.M.); (K.N.S.); (W.C.W.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Matthew A. Ciorba
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA;
- Division of Gastroenterology, Department of Medicine, Washington School of Medicine, St. Louis, MO 63110, USA
| | - Jonathan B. Mitchem
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65201, USA; (Y.I.N.); (C.-R.S.); (J.T.K.)
- Department of Surgery, Columbia, MO 65212, USA; (Y.M.); (K.N.S.); (W.C.W.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA;
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21
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Hanus M, Parada-Venegas D, Landskron G, Wielandt AM, Hurtado C, Alvarez K, Hermoso MA, López-Köstner F, De la Fuente M. Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment. Front Immunol 2021; 12:612826. [PMID: 33841394 PMCID: PMC8033001 DOI: 10.3389/fimmu.2021.612826] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/02/2021] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals (cytokines, chemokines or growth factors) to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet-derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as pks+ Escherichia coli or Fusobacterium nucleatum, are involved in colorectal carcinogenesis through different pathomechanisms including the induction of genetic mutations in epithelial cells and modulation of tumor microenvironment. Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.
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Affiliation(s)
- Michelle Hanus
- Laboratory of Innate Immunity, Program of Immunology, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile
| | - Daniela Parada-Venegas
- Laboratory of Innate Immunity, Program of Immunology, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile
| | - Glauben Landskron
- Laboratory of Innate Immunity, Program of Immunology, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile
| | | | - Claudia Hurtado
- Research Core, Academic Department, Clínica Las Condes, Santiago, Chile
| | - Karin Alvarez
- Cancer Center, Clínica Universidad de los Andes, Santiago, Chile
| | - Marcela A. Hermoso
- Laboratory of Innate Immunity, Program of Immunology, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile
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22
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MacLachlan BJ, Mason GH, Greenshields‐Watson A, Triebel F, Gallimore A, Cole DK, Godkin A. Molecular characterization of HLA class II binding to the LAG-3 T cell co-inhibitory receptor. Eur J Immunol 2021; 51:331-341. [PMID: 32920841 PMCID: PMC8101287 DOI: 10.1002/eji.202048753] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/24/2020] [Accepted: 09/11/2020] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors (antibodies that block the T cell co-inhibitory receptors PD-1/PD-L1 or CTLA-4) have revolutionized the treatment of some forms of cancer. Importantly, combination approaches using drugs that target both pathways have been shown to boost the efficacy of such treatments. Subsequently, several other T cell inhibitory receptors have been identified for the development of novel immune checkpoint inhibitors. Included in this list is the co-inhibitory receptor lymphocyte activation gene-3 (LAG-3), which is upregulated on T cells extracted from tumor sites that have suppressive or exhausted phenotypes. However, the molecular rules that govern the function of LAG-3 are still not understood. Using surface plasmon resonance combined with a novel bead-based assay (AlphaScreenTM ), we demonstrate that LAG-3 can directly and specifically interact with intact human leukocyte antigen class II (HLA-II) heterodimers. Unlike the homologue CD4, which has an immeasurably weak affinity using these biophysical approaches, LAG-3 binds with low micromolar affinity. We further validated the interaction at the cell surface by staining LAG-3+ cells with pHLA-II-multimers. These data provide new insights into the mechanism by which LAG-3 initiates T cell inhibition.
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Affiliation(s)
| | | | | | | | - Awen Gallimore
- Division of Infection & ImmunityCardiff UniversityCardiffUK
| | - David K. Cole
- Division of Infection & ImmunityCardiff UniversityCardiffUK
| | - Andrew Godkin
- Division of Infection & ImmunityCardiff UniversityCardiffUK
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23
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Khan A, Dias F, Neekhra S, Singh B, Srivastava R. Designing and Immunomodulating Multiresponsive Nanomaterial for Cancer Theranostics. Front Chem 2021; 8:631351. [PMID: 33585406 PMCID: PMC7878384 DOI: 10.3389/fchem.2020.631351] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 12/22/2020] [Indexed: 01/14/2023] Open
Abstract
Cancer has been widely investigated yet limited in its manifestation. Cancer treatment holds innovative and futuristic strategies considering high disease heterogeneity. Chemotherapy, radiotherapy and surgery are the most explored pillars; however optimal therapeutic window and patient compliance recruit constraints. Recently evolved immunotherapy demonstrates a vital role of the host immune system to prevent metastasis recurrence, still undesirable clinical response and autoimmune adverse effects remain unresolved. Overcoming these challenges, tunable biomaterials could effectively control the co-delivery of anticancer drugs and immunomodulators. Current status demands a potentially new approach for minimally invasive, synergistic, and combinatorial nano-biomaterial assisted targeted immune-based treatment including therapeutics, diagnosis and imaging. This review discusses the latest findings of engineering biomaterial with immunomodulating properties and implementing novel developments in designing versatile nanosystems for cancer theranostics. We explore the functionalization of nanoparticle for delivering antitumor therapeutic and diagnostic agents promoting immune response. Through understanding the efficacy of delivery system, we have enlightened the applicability of nanomaterials as immunomodulatory nanomedicine further advancing to preclinical and clinical trials. Future and present ongoing improvements in engineering biomaterial could result in generating better insight to deal with cancer through easily accessible immunological interventions.
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Affiliation(s)
- Amreen Khan
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
- Centre for Research in Nanotechnology and Science, Indian Institute of Technology Bombay, Mumbai, India
| | - Faith Dias
- Department of Chemical Engineering, Thadomal Shahani Engineering College, Mumbai, India
| | - Suditi Neekhra
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Barkha Singh
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
- Centre for Research in Nanotechnology and Science, Indian Institute of Technology Bombay, Mumbai, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
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24
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Tumor-Infiltrating Lymphoid Cells in Colorectal Cancer Patients with Varying Disease Stages and Microsatellite Instability-High/Stable Tumors. Vaccines (Basel) 2021; 9:vaccines9010064. [PMID: 33477864 PMCID: PMC7832866 DOI: 10.3390/vaccines9010064] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/10/2021] [Accepted: 01/15/2021] [Indexed: 12/24/2022] Open
Abstract
Immune checkpoint inhibition is an effective anti-cancer therapeutic approach but has shown limited efficacy in treating colorectal cancer (CRC) patients. Importantly, immune constituents of the tumor microenvironment (TME) can influence therapy response and cancer progression. We investigated the expression of immune checkpoints (ICs) on lymphoid populations within the CRC TME and compared with cells from normal colon tissues using samples from 50 patients with varying disease stages. We found that the levels of B cells, T cells, and NK cells were similar, IC-expressing CD4+ and CD4+CD8+ double positive T cells were higher, while CD8+ T cells and CD4−CD8− double negative T cells were significantly lower in CRC tumors. Notably, patients with mismatch-repair deficiency/microsatellite instability-high tumors had higher levels of IC-expressing CD4+ and CD8+ T cells than patients with proficient MMR and microsatellite stable tumors. Lastly, The Cancer Genome Atlas Colon Adenocarcinoma datasets showed associations between low expression of selective genes and poorer progression-free interval. Our findings highlight differential expression of ICs on lymphoid cells in CRC tumors in the era of cancer immunotherapy, which at present is solely approved for anti-PD-1 therapy in patients with dMMR/MSI-H tumors. Further investigations into their functionality have potentials for deciphering resistance mechanisms to IC inhibition.
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25
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Kolb HR, Borcherding N, Zhang W. Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:229-256. [PMID: 33523451 DOI: 10.1007/978-981-15-6407-9_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Regulatory T cells (Tregs) are critical in maintaining immune homeostasis under various pathophysiological conditions. A growing body of evidence demonstrates that Tregs play an important role in cancer progression and that they do so by suppressing cancer-directed immune responses. Tregs have been targeted for destruction by exploiting antibodies against and small-molecule inhibitors of several molecules that are highly expressed in Tregs-including immune checkpoint molecules, chemokine receptors, and metabolites. To date, these strategies have had only limited antitumor efficacy, yet they have also created significant risk of autoimmunity because most of them do not differentiate Tregs in tumors from those in normal tissues. Currently, immune checkpoint inhibitor (ICI)-based cancer immunotherapies have revolutionized cancer treatment, but the resistance to ICI is common and the elevation of Tregs is one of the most important mechanisms. Therapeutic strategies that can selectively eliminate Tregs in the tumor (i.e. therapies that do not run the risk of causing autoimmunity by affecting normal tissue), are urgently needed for the development of cancer immunotherapies. This chapter discusses specific properties of human Tregs under the context of cancer and the various ways to target Treg for cancer immunotherapy.
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Affiliation(s)
- H Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Nicholas Borcherding
- Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
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26
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Sarkar T, Dhar S, Sa G. Tumor-infiltrating T-regulatory cells adapt to altered metabolism to promote tumor-immune escape. CURRENT RESEARCH IN IMMUNOLOGY 2021; 2:132-141. [PMID: 35492399 PMCID: PMC9040151 DOI: 10.1016/j.crimmu.2021.08.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/16/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor mass and its microenvironment alter host immune system in various ways to promote tumor growth. One of the modifications is evasion of immune surveillance by augmenting the number of Tregs in tumor vicinity. Elevated levels of Tregs are seen in peripheral circulation and tumor tissue of cancer patients. Cancer cells release several chemokines to attract Tregs in tumor-site. Infiltration of Tregs has clinical significance because being immunosuppressive infiltrating Tregs suppress other immune cells making the tumor microenvironment favorable for tumor growth. On the other hand, infiltrating Tregs show metabolic alteration in tumor microenvironment which allows their selective survival over the others. Persistence of Tregs in the tumor microenvironment and subsequent immunosuppression makes Tregs a potential therapeutic obstacle and the reason behind the failure of immunotherapy. In this review, we emphasize the recent development in the metabolic adaptation of tumor-infiltrating Tregs and the therapeutic approaches to boost immunity against cancer.
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27
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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28
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Lauder SN, Smart K, Kersemans V, Allen D, Scott J, Pires A, Milutinovic S, Somerville M, Smart S, Kinchesh P, Lopez-Guadamillas E, Hughes E, Jones E, Scurr M, Godkin A, Friedman LS, Vanhaesebroeck B, Gallimore A. Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3. J Immunother Cancer 2020; 8:e000693. [PMID: 33093155 PMCID: PMC7583804 DOI: 10.1136/jitc-2020-000693] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. METHODS Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. RESULTS As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8+ T cells, T cell factor 1 (TCF1)+ T cells and CD69- T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3Kδ and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3Kδ inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3Kδ inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies. CONCLUSIONS These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.
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Affiliation(s)
- Sarah Nicol Lauder
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | - Kathryn Smart
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | | | - Danny Allen
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - Jake Scott
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | - Ana Pires
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | - Stefan Milutinovic
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | - Michelle Somerville
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | - Sean Smart
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - Paul Kinchesh
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | | | - Ellyn Hughes
- Cancer Biomarker Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Emma Jones
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | - Martin Scurr
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | - Andrew Godkin
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
| | | | - Bart Vanhaesebroeck
- UCL Cancer Institute, Paul O'Gorman Building, University College London, London, UK
| | - Awen Gallimore
- Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK
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29
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Giatromanolaki A, Kouroupi M, Pouliliou S, Mitrakas A, Hasan F, Pappa A, Koukourakis MI. Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways. Life Sci 2020; 259:118389. [PMID: 32898522 DOI: 10.1016/j.lfs.2020.118389] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/24/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023]
Abstract
AIMS Adenosine triphosphate (ATP) is released at a high concentration in the tumor microenvironment. The overexpression of ectonucleotidases in non-small-cell lung cancer (NSCLC), metabolizing ΑΤP to the immunosuppressive adenosine, is studied. MATERIALS AND METHODS We examined the expression of the ectonucleotidases CD73 and CD39 in NSCLC in parallel with immunological parameters and markers of hypoxia and anaerobic metabolism. In vitro experiments with A549 and H1299 lung cancer cell lines were also conducted. RESULTS CD73 and CD39 were not expressed by normal bronchial and alveolar epithelium. In contrast, these were overexpressed by cancer cells, cancer-associated fibroblasts (CAFs), and tumor-infiltrating lymphocytes (TILs). High CD73 cancer cell expression was directly linked with lactate dehydrogenase LDH5 and with hypoxia-inducible factor HIF1α expression by cancer cells. The expression of CD39 by CAFs was directly linked with PD-L1 expression by cancer cells. A significant abundance of FOXP3+ and PD-1+ TILs was noted in tumors with high CD73 and CD39 stroma expression. In in vitro experiments, hypoxia and acidity induced CD73 mRNA and protein levels in cancer cell lines. Exposure of cancer cell lines to adenosine induced the expression of PD-L1 and LDHA mRNA and protein levels. CONCLUSION Ectonucleotidases are up-regulated in cancer cells, CAFs, and TILs in lung tumors. Such overexpression is linked with regulatory TIL-phenotype and PD-L1 up-regulation by cancer cells. Overexpression of LDH5 is up-regulated by adenosine, creating a vicious cycle, as the high amounts of ATP produced by LDH5-mediated anaerobic glycolysis promote the production of adenosine by a tumor microenvironment rich in ectonucleotidases.
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Affiliation(s)
- Alexandra Giatromanolaki
- Department of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
| | - Maria Kouroupi
- Department of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Stamatia Pouliliou
- Department of Radiotherapy/Oncology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Achilleas Mitrakas
- Department of Radiotherapy/Oncology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Fatma Hasan
- Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus Dragana, 68100 Alexandroupolis, Greece
| | - Aglaia Pappa
- Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus Dragana, 68100 Alexandroupolis, Greece
| | - Michael I Koukourakis
- Department of Radiotherapy/Oncology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
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30
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Genomic profile and immune contexture in colorectal cancer-relevance for prognosis and immunotherapy. Clin Exp Med 2020; 21:195-204. [PMID: 32720224 DOI: 10.1007/s10238-020-00649-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 07/17/2020] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) is one of the leading cancers in both genders. TNM staging system is still the most commonly used tumor classification and prognostic system. The disadvantage of TNM is that the prognostic information it provides is incomplete, and patients with the same histological tumor stages may differ significantly in the clinical outcome. Therefore, the identification of new prognostic parameters is crucial. The carcinogenic process that gives rise to an individual tumor is unique and tumor microenviroment should be taken into consideration. In CRC, T-cell infiltration is not homogenous, and recent studies are mostly focusing on memory T-cells and CD8 cells in predicting disease-free survival (DFS) and overall survival (OS). It seems that DFS and OS are not only dependent on microsatellite instable or stable status but mostly on the levels of expression of the immune signatures. Also, patients with high infiltration of cytotoxic and memory cells have significantly better outcome. This review consolidates current knowledge and recent research about importance of immune-cell-associated proteins, specific gene profiles of immune cells and immunotherapy in CRC. We also discussed cell-specific signatures in cancer treatment.
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31
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Olguín JE, Medina-Andrade I, Rodríguez T, Rodríguez-Sosa M, Terrazas LI. Relevance of Regulatory T Cells during Colorectal Cancer Development. Cancers (Basel) 2020; 12:E1888. [PMID: 32674255 PMCID: PMC7409056 DOI: 10.3390/cancers12071888] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/21/2020] [Accepted: 07/01/2020] [Indexed: 12/14/2022] Open
Abstract
In recent years, there has been a significant increase in the study of own and foreign human factors favoring the development of different types of cancer, including genetic and environmental ones. However, the fact that the immune response plays a fundamental role in the development of immunity and susceptibility to colorectal cancer (CRC) is much stronger. Among the many cell populations of the immune system that participate in restricting or favoring CRC development, regulatory T cells (Treg) play a major role in orchestrating immunomodulation during CRC. In this review, we established concrete evidence supporting the fact that Treg cells have an important role in the promotion of tumor development during CRC, mediating an increasing suppressive capacity which controls the effector immune response, and generating protection for tumors. Furthermore, Treg cells go through a process called "phenotypic plasticity", where they co-express transcription factors that promote an inflammatory profile. We reunited evidence that describes the interaction between the different effector populations of the immune response and its modulation by Treg cells adapted to the tumor microenvironment, including the mechanisms used by Treg cells to suppress the protective immune response, as well as the different subpopulations of Treg cells participating in tumor progression, generating susceptibility during CRC development. Finally, we discussed whether Treg cells might or might not be a therapeutic target for an effective reduction in the morbidity and mortality caused by CRC.
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Affiliation(s)
- Jonadab E. Olguín
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
- Unidad de Biomedicina, FES Iztacala, UNAM, Av. De los Barrios # 1, Tlalnepantla 54090, Mexico
| | - Itzel Medina-Andrade
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
- Unidad de Biomedicina, FES Iztacala, UNAM, Av. De los Barrios # 1, Tlalnepantla 54090, Mexico
| | - Tonathiu Rodríguez
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
| | - Miriam Rodríguez-Sosa
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
| | - Luis I. Terrazas
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
- Unidad de Biomedicina, FES Iztacala, UNAM, Av. De los Barrios # 1, Tlalnepantla 54090, Mexico
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NKG2D-Fc fusion protein promotes antitumor immunity through the depletion of immunosuppressive cells. Cancer Immunol Immunother 2020; 69:2147-2155. [PMID: 32468232 DOI: 10.1007/s00262-020-02615-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Accepted: 05/16/2020] [Indexed: 12/15/2022]
Abstract
A major factor impeding the success of numerous therapeutic approaches in cancer is the immunosuppressive nature of the tumor microenvironment (TME). Hence, methods capable of reverting tumor immunosuppression through depletion or reprogramming of myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) are of great clinical need. Here, we explore NKG2D-Fc as a modality to modulate antitumor immunity through the depletion of immunosuppressive MDSCs and Tregs in the TME. We have generated the NKG2D-Fc fusion protein and characterized its potential to mediate tumor control and overall survival in LL2 and MC38 murine models. Upon treatment of LL2 or MC38 tumor-bearing mice with NKG2D-Fc, we observe significant tumor control and enhanced survival compared to Fc control. When characterizing MDCSs and Tregs from tumor-bearing mice, we observe clear expression of NKG2D-ligand RAE1γ and subsequent binding of NKG2D-Fc fusion protein to both MDSCs and Tregs. Examining the immune profile of mice treated with NKG2D-Fc reveals significant depletion of MDSCs and Tregs in the TME, as well as an increase in NK cells likely due to the reversed suppressive TME. In conclusion, NKG2D-Fc induces antitumor immunity and tumor control through the depletion of MDSCs and Tregs, subsequently providing a niche for the infiltration and expansion of proinflammatory cells, such as NK cells. Strategies capable of modulating the immunosuppressive state in cancer are in high clinical demand. NKG2D-Fc is a simple, single tool capable of depleting both MDSCs and Tregs and should be further investigated as a therapeutic agent for the treatment of cancer.
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Čolić M, Tomić S, Bekić M. Immunological aspects of nanocellulose. Immunol Lett 2020; 222:80-89. [PMID: 32278785 DOI: 10.1016/j.imlet.2020.04.004] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/21/2020] [Accepted: 04/04/2020] [Indexed: 12/31/2022]
Abstract
Cellulose is the most abundant natural polymer in the world. Nanoscale forms of cellulose, including cellulose nanofibers (CNF), cellulose nanocrystals (CNC) and bacterial nanocellulose (BC), are very attractive in industry, medicine and pharmacy. Biomedical applications of nanocellulose in tissue engineering, regenerative medicine, and controlled drug delivery are the most promising. Nanocellulose is considered a biocompatible nanomaterial and relatively safe for biomedical applications. However, more studies are needed to prove this hypothesis, especially those related to chronic exposure to nanocellulose. Besides toxicity, the response of the immune system is of particular importance in this sense. This paper provides a comprehensive and critical review of the current-state knowledge of the impact of nanocellulose on the immune system, especially on macrophages and dendritic cells (DC), as the central immunoregulatory cells, which has not been addressed in the literature sufficiently. Nanocellulose, especially CNC, can induce the inflammatory response upon the internalization by macrophages, but this reaction may be significantly modulated by introducing different functional groups on their surface. Our original results showed that nanocellulose has a potent immunotolerogenic potential. Native CNF potentiated the capacity of DC to induce conventional Tregs. When carboxyl groups were introduced on the CNF surface, the tolerogenic potential of DC was shifted towards the induction of regulatory CD8+ T cells, whereas the introduction of phosphonates on CNF surface potentiated DCs' capacity to induce both regulatory CD8+ T cells and Type 1 regulatory (Tr-1) cells. These results are extremely important when considering the application of nanocellulose in vivo, especially for tissue regeneration and wound healing.
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Affiliation(s)
- Miodrag Čolić
- Institute for the Application of Nuclear Energy, University of Belgrade, Serbia; University of East Sarajevo, Medical Faculty Foča, R.Srpska, BiH; Serbian Academy of Sciences and Arts, Belgrade, Serbia.
| | - Sergej Tomić
- Institute for the Application of Nuclear Energy, University of Belgrade, Serbia
| | - Marina Bekić
- Institute for the Application of Nuclear Energy, University of Belgrade, Serbia
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Lymphocyte activation gene 3 (LAG3) protein expression on tumor-infiltrating lymphocytes in aggressive and TP53-mutated salivary gland carcinomas. Cancer Immunol Immunother 2020; 69:1363-1373. [PMID: 32232506 PMCID: PMC7370910 DOI: 10.1007/s00262-020-02551-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 03/17/2020] [Indexed: 12/16/2022]
Abstract
Salivary gland carcinomas (SGCs) are rare and can be subdivided into distinct entities, some of which confer a poor prognosis. As targets for effective systemic therapy are warranted, some studies investigated the role of immune-checkpoint proteins PD-L1 and CTLA-4 in SGC. Our study depicts the expression of lymphocyte activation gene 3 (LAG3) in a test cohort and a larger validation cohort, totaling 139 SGCs. LAG3 is expressed on tumor-infiltrating lymphocytes (TILs), mediates T cell exhaustion and is subject to numerous currently recruiting clinical studies. Overall, one-third of SGCs were infiltrated by LAG3-expressing TILs with a strikingly high concordance between the test cohort and the validation cohort (30% and 28.2%, respectively). In the validation cohort, entity-wise LAG3 expression frequencies were highly variable. The highest rates were observed in salivary duct carcinoma (SDC; 66.7%) and adenocarcinoma not otherwise specified (ANOS; 50.0%). We observed LAG3 expression on effector T cells and in smaller frequencies also on FOXP3− T helper cells and FOXP3+ Tregs. LAG3 expression significantly correlated with advanced nodal metastases, cytotoxic T cell infiltrate and TP53 mutations. In the group of adenoid cystic carcinomas, LAG3 expression was also associated with a shorter event-free survival (EFS). Tumors with TP53 nonsense mutations (TP53 null type) exhibited higher LAG3 frequencies and a shorter EFS compared to TP53 wild type. This is the first report of LAG3 expression in SGC, a promising target for immunotherapy. LAG3 blockage could be distinctly applicable for SDC and ANOS, two SGC types with a particularly poor outcome.
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35
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Picard E, Verschoor CP, Ma GW, Pawelec G. Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer. Front Immunol 2020; 11:369. [PMID: 32210966 PMCID: PMC7068608 DOI: 10.3389/fimmu.2020.00369] [Citation(s) in RCA: 334] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/17/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.
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Affiliation(s)
- Emilie Picard
- Health Sciences North Research Institute, Sudbury, ON, Canada
| | | | - Grace W Ma
- Department of Surgery, Health Sciences North, Sudbury, ON, Canada
| | - Graham Pawelec
- Health Sciences North Research Institute, Sudbury, ON, Canada.,Department of Immunology, University of Tübingen, Tübingen, Germany
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36
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Kim JH, Kim BS, Lee SK. Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy. Immune Netw 2020; 20:e4. [PMID: 32158592 PMCID: PMC7049587 DOI: 10.4110/in.2020.20.e4] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 01/30/2020] [Accepted: 02/02/2020] [Indexed: 12/21/2022] Open
Abstract
Tregs have a role in immunological tolerance and immune homeostasis by suppressing immune reactions, and its therapeutic potential is critical in autoimmune diseases and cancers. There have been multiple studies conducted on Tregs because of their roles in immune suppression and therapeutic potential. In tumor immunity, Tregs can promote the development and progression of tumors by preventing effective anti-tumor immune responses in tumor-bearing hosts. High infiltration of Tregs into tumor tissue results in poor survival in various types of cancer patients. Identifying factors specifically expressed in Tregs that affect the maintenance of stability and function of Tregs is important for understanding cancer pathogenesis and identifying therapeutic targets. Thus, manipulation of Tregs is a promising anticancer strategy, but finding markers for Treg-specific depletion and controlling these cells require fine-tuning and further research. Here, we discuss the role of Tregs in cancer and the development of Treg-targeted therapies to promote cancer immunotherapy.
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Affiliation(s)
- Jung-Ho Kim
- Research Institute for Precision Immune-Medicine, Good T Cells, Inc., Seoul 03722, Korea
| | - Beom Seok Kim
- Research Institute for Precision Immune-Medicine, Good T Cells, Inc., Seoul 03722, Korea
| | - Sang-Kyou Lee
- Research Institute for Precision Immune-Medicine, Good T Cells, Inc., Seoul 03722, Korea
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
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37
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Perez-Santos M, Anaya-Ruiz M, Cebada J, Bandala C, Landeta G, Martínez-Morales P, Villa-Ruano N. LAG-3 antagonists by cancer treatment: a patent review. Expert Opin Ther Pat 2019; 29:643-651. [DOI: 10.1080/13543776.2019.1642873] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Martin Perez-Santos
- Oficina de Comercialización de Tecnología, Centro Universitario de Vinculación y Transferencia de Tecnología, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Maricruz Anaya-Ruiz
- Laboratorio de Biología Celular, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Metepec, Puebla, Mexico
| | - Jorge Cebada
- Facultad de Medicina, Benémerita Universidad Autónoma de Puebla, Puebla, México
| | - Cindy Bandala
- Departamento de Neuurociencias, Instituto Nacional de Rehabilitación, Ciudad de México, Mexico
| | - Gerardo Landeta
- Coordinación de Investigación Aplicada, Centro Universitario de Vinculación y Transferencia de Tecnología, Benemérita Universidad Autónoma de Puebla, Puebla, México
| | - Patricia Martínez-Morales
- CONACYT-Instituto Mexicano del Seguro Social - Laboratorio de Biología Molecular, Centro de Investigación Biomédica de Oriente, Metepec, Puebla, Mexico
| | - Nemesio Villa-Ruano
- CONACYT-Coordinación de Investigación Aplicada, Centro Universitario de Vinculación y Transferencia de Tecnología, Benemérita Universidad Autónoma de Puebla, Puebla, México
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38
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Perez-Santos M, Anaya-Ruiz M, Cebada J, Herrera-Camacho I. Treatment of cancer with a combination of LAG-3Ig and anti-PD-1/anti-PD-L1 antibodies: a patent evaluation of US2018271940 A1. Expert Opin Ther Pat 2019; 29:311-314. [DOI: 10.1080/13543776.2019.1608947] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Martin Perez-Santos
- Oficina de Comercialización de Tecnología, Centro Universitario de Vinculación y Transferencia de Tecnología, Benemérita Universidad Autónoma de Puebla, Puebla, México
| | - Maricruz Anaya-Ruiz
- Laboratorio de Biología Celular, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Metepec, Puebla, Mexico
| | - Jorge Cebada
- Facultad de Medicina, Benémerita Universidad Autónoma de Puebla, Puebla, México
| | - Irma Herrera-Camacho
- Laboratorio de Bioquímica, Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, México
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39
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Adah D, Yang Y, Liu Q, Gadidasu K, Tao Z, Yu S, Dai L, Li X, Zhao S, Qin L, Qin L, Chen X. Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model. Cell Commun Signal 2019; 17:32. [PMID: 30979375 PMCID: PMC6461823 DOI: 10.1186/s12964-019-0342-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 03/14/2019] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown. METHODS Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells were harvested 17 days post tumor implantation and analyzed using QPCR, western blotting, flow cytometry, and functional assays. Differences between groups were analyzed for statistical significance using Student's t-test. RESULTS Here we found that Plasmodium infection significantly reduced the proportions of MDSCs and Tregs in the lung tumor tissues of the treated mice by downregulating their recruiting molecules and blocking cellular activation pathways. Importantly, CD8+ T cells isolated from the tumors of Plasmodium-treated mice exhibited significantly higher levels of granzyme B and perforin and remarkably lower levels of PD-1. CONCLUSION We reveal for the first time, the effects of Plasmodium infection on the expansion and activation of MDSCs and Tregs with a consequent elevation of CD8+T cell-mediated cytotoxicity within the tumor microenvironment and hold great promise for the development of effective immunotherapeutic strategies.
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Affiliation(s)
- Dickson Adah
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.,University of Chinese Academy of Sciences, No. 190 Yuquan Road, Beijing, 100049, People's Republic of China
| | - Yijun Yang
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.,University of Chinese Academy of Sciences, No. 190 Yuquan Road, Beijing, 100049, People's Republic of China
| | - Quan Liu
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.,University of Chinese Academy of Sciences, No. 190 Yuquan Road, Beijing, 100049, People's Republic of China
| | - Kranthi Gadidasu
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China
| | - Zhu Tao
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China
| | - Songlin Yu
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.,University of Chinese Academy of Sciences, No. 190 Yuquan Road, Beijing, 100049, People's Republic of China
| | - Linglin Dai
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.,Guangzhou Regenerative Medicine and Health-Guangdong Laboratory GRMH-GDL, Guangzhou, 510530, People's Republic of China
| | - Xiaofen Li
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.,Guangzhou Regenerative Medicine and Health-Guangdong Laboratory GRMH-GDL, Guangzhou, 510530, People's Republic of China
| | - Siting Zhao
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.,Guangzhou Regenerative Medicine and Health-Guangdong Laboratory GRMH-GDL, Guangzhou, 510530, People's Republic of China
| | - Limei Qin
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China
| | - Li Qin
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China. .,Guangzhou Regenerative Medicine and Health-Guangdong Laboratory GRMH-GDL, Guangzhou, 510530, People's Republic of China.
| | - Xiaoping Chen
- State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China. .,Guangzhou Regenerative Medicine and Health-Guangdong Laboratory GRMH-GDL, Guangzhou, 510530, People's Republic of China.
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40
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Gliwiński M, Piotrowska M, Iwaszkiewicz-Grześ D, Urban-Wójciuk Z, Trzonkowski P. Therapy with CD4 +CD25 + T regulatory cells - should we be afraid of cancer? Contemp Oncol (Pozn) 2019; 23:1-6. [PMID: 31061630 PMCID: PMC6500397 DOI: 10.5114/wo.2019.84110] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 03/24/2019] [Indexed: 12/27/2022] Open
Abstract
This review focuses on the role of regulatory T cells (Tregs) in the process of carcinogenesis. The controversy of this issue arose due to the increasing therapeutic use of Tregs in humans (inter alia, in the treatment of autoimmune diseases). It is mainly due to potential dangers related to immunosuppressive activity of these cells, especially regarding cancer. The natural function of regulatory T cells (which is the suppression of excessive activity of the immune system) is purportedly linked to an increased risk of cancer initiation. This work brings together and summarizes the most important reports of researchers dealing with this problem and attempts to explain doubts and fears related to Tregs and their uncertain connection with cancer initiation and progression. It is clearly shown that regulatory T cells are associated with acceleration of existing tumors (they are attracted by microenvironments created by cancer cells) but cannot initiate them on their own.
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Affiliation(s)
- Mateusz Gliwiński
- Department of Medical Immunology, Medical University of Gdansk, Gdansk, Poland
| | | | | | - Zuzanna Urban-Wójciuk
- International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland
| | - Piotr Trzonkowski
- Department of Medical Immunology, Medical University of Gdansk, Gdansk, Poland
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41
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Visekruna A, Hartmann S, Sillke YR, Glauben R, Fischer F, Raifer H, Mollenkopf H, Bertrams W, Schmeck B, Klein M, Pagenstecher A, Lohoff M, Jacob R, Pabst O, Bland PW, Luu M, Romero R, Siegmund B, Rajalingam K, Steinhoff U. Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cells. J Clin Invest 2019; 129:1972-1983. [PMID: 30939122 DOI: 10.1172/jci98929] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 02/19/2019] [Indexed: 12/30/2022] Open
Abstract
The impact of food antigens on intestinal homeostasis and immune function is poorly understood. Here, we explored the impact of dietary antigens on the phenotype and fate of intestinal T cells. Physiological uptake of dietary proteins generated a highly activated CD44+Helios+CD4+ T cell population predominantly in Peyer patches. These cells are distinct from regulatory T cells and develop independently of the microbiota. Alimentation with a protein-free, elemental diet led to an atrophic small intestine with low numbers of activated T cells, including Tfh cells and decreased amounts of intestinal IgA and IL-10. Food-activated CD44+Helios+CD4+ T cells in the Peyer patches are controlled by the immune checkpoint molecule PD-1. Blocking the PD-1 pathway rescued these T cells from apoptosis and triggered proinflammatory cytokine production, which in IL-10-deficient mice was associated with intestinal inflammation. In support of these findings, our study of patients with Crohn's disease revealed significantly reduced frequencies of apoptotic CD4+ T cells in Peyer patches as compared with healthy controls. These results suggest that apoptosis of diet-activated T cells is a hallmark of the healthy intestine.
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Affiliation(s)
- Alexander Visekruna
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Sabrina Hartmann
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Yasmina Rodriguez Sillke
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Germany
| | - Rainer Glauben
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Germany
| | - Florence Fischer
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Hartmann Raifer
- Flow Cytometry Core Facility, Philipps University Marburg, Germany
| | - Hans Mollenkopf
- Max Planck Institute for Infection Biology, Core Facility Microarray/Genomics, Berlin, Germany
| | - Wilhelm Bertrams
- Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Philipps University Marburg, Germany
| | - Bernd Schmeck
- Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Philipps University Marburg, Germany
| | - Matthias Klein
- Institute for Immunology, University Medical Center, Mainz, Germany
| | - Axel Pagenstecher
- Department of Neuropathology, Philipps University of Marburg, Germany
| | - Michael Lohoff
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Ralf Jacob
- Department of Cell Biology and Cell Pathology, Philipps University of Marburg, Germany
| | - Oliver Pabst
- Institute of Molecular Medicine, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
| | - Paul William Bland
- Department of Microbiology & Immunology, Gothenburg University, Gothenburg, Sweden
| | - Maik Luu
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Rossana Romero
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Britta Siegmund
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Germany
| | | | - Ulrich Steinhoff
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
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Barilla RM, Diskin B, Caso RC, Lee KB, Mohan N, Buttar C, Adam S, Sekendiz Z, Wang J, Salas RD, Cassini MF, Karlen J, Sundberg B, Akbar H, Levchenko D, Gakhal I, Gutierrez J, Wang W, Hundeyin M, Torres-Hernandez A, Leinwand J, Kurz E, Rossi JAK, Mishra A, Liria M, Sanchez G, Panta J, Loke P, Aykut B, Miller G. Specialized dendritic cells induce tumor-promoting IL-10 +IL-17 + FoxP3 neg regulatory CD4 + T cells in pancreatic carcinoma. Nat Commun 2019; 10:1424. [PMID: 30926808 PMCID: PMC6441038 DOI: 10.1038/s41467-019-09416-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 02/14/2019] [Indexed: 12/18/2022] Open
Abstract
The drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103- DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b+CD103- DC promote CD4+ T cell tolerance in PDA which may underscore its resistance to immunotherapy.
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Affiliation(s)
- Rocky M Barilla
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Brian Diskin
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Raul Caso Caso
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Ki Buom Lee
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Navyatha Mohan
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Chandan Buttar
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Salma Adam
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Zennur Sekendiz
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Junjie Wang
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Ruben D Salas
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Marcelo F Cassini
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Jason Karlen
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Belen Sundberg
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Hashem Akbar
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Dmitry Levchenko
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Inderdeep Gakhal
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Johana Gutierrez
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Wei Wang
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Mautin Hundeyin
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Alejandro Torres-Hernandez
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Joshua Leinwand
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Emma Kurz
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Juan A Kochen Rossi
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Ankita Mishra
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Miguel Liria
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Gustavo Sanchez
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Jyoti Panta
- Department of Microbiology, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - P'ng Loke
- Department of Microbiology, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - Berk Aykut
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA
| | - George Miller
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA.
- Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA.
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43
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Tomić S, Joksimović B, Bekić M, Vasiljević M, Milanović M, Čolić M, Vučević D. Prostaglanin-E2 Potentiates the Suppressive Functions of Human Mononuclear Myeloid-Derived Suppressor Cells and Increases Their Capacity to Expand IL-10-Producing Regulatory T Cell Subsets. Front Immunol 2019; 10:475. [PMID: 30936876 PMCID: PMC6431635 DOI: 10.3389/fimmu.2019.00475] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/21/2019] [Indexed: 01/22/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSC) emerged as major factors driving the tumor progression due to numerous immunosuppressive mechanisms they possess. Prostaglandin (PG)E2 is shown critical for the induction of MDSC and their suppressive functions in vivo, but it is poorly understood how it affects the capacity of MDSC to induce different subsets of regulatory T cells (Treg). By using a novel protocol for the generation of mononuclear (M)-MDSC, we showed that PGE2 potentiates the GM-CSF/IL-6-dependent induction of CD33+CD11b+HLA-DR-CD14+ M-MDSC in vitro. PGE2 diminished the capacity of GM-CSF/IL-6 M-MDSC to produce proinflammatory cytokines upon activation and augmented their capacity to produce IL-27, IL-33, and TGF-β. These results correlated with an increased potential of GM-CSF/IL-6/PGE2 M-MDSC to suppress T cell proliferation, expand alloreactive Th2 cells, and reduce the development of alloreactive Th17 and cytotoxic T cells. Interestingly, GM-CSF/IL-6/PGE2 M-MDSC displayed a lower capacity to induce TGF-β-producing FoxP3+ regulatory Treg compared to GM-CSF/IL-6 M-MDSC, as a consequence of reduced IDO-1 expression. In contrast, GM-CSF/IL-6/PGE2 M-MDSC potentiated IL-10 production by CD8+T, Th2, and particularly CD4+FoxP3- type 1 Treg, the latter of which depended on ILT3 and ILT4 expression. Cumulatively, PGE2 potentiated the suppressive phenotype and functions of GM-CSF/IL-6-induced M-MDSC and changed the mechanisms involved in Treg induction, which could be important for investigating new therapeutic strategies focused on MDSC-related effects in tumors and autoimmune diseases.
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Affiliation(s)
- Sergej Tomić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
- Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Belgrade, Serbia
| | - Bojan Joksimović
- Medical Faculty Foča, University of East Sarajevo, Lukavica, Bosnia and Herzegovina
| | - Marina Bekić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
- Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Belgrade, Serbia
| | - Miloš Vasiljević
- Medical Faculty Foča, University of East Sarajevo, Lukavica, Bosnia and Herzegovina
| | - Marijana Milanović
- Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Belgrade, Serbia
| | - Miodrag Čolić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
- Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Belgrade, Serbia
- Medical Faculty Foča, University of East Sarajevo, Lukavica, Bosnia and Herzegovina
| | - Dragana Vučević
- Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Belgrade, Serbia
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44
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Norton SE, Ward-Hartstonge KA, McCall JL, Leman JKH, Taylor ES, Munro F, Black MA, Fazekas de St. Groth B, McGuire HM, Kemp RA. High-Dimensional Mass Cytometric Analysis Reveals an Increase in Effector Regulatory T Cells as a Distinguishing Feature of Colorectal Tumors. THE JOURNAL OF IMMUNOLOGY 2019; 202:1871-1884. [DOI: 10.4049/jimmunol.1801368] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 01/14/2019] [Indexed: 12/20/2022]
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45
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Besneux M, Greenshields-Watson A, Scurr MJ, MacLachlan BJ, Christian A, Davies MM, Hargest R, Phillips S, Godkin A, Gallimore A. The nature of the human T cell response to the cancer antigen 5T4 is determined by the balance of regulatory and inflammatory T cells of the same antigen-specificity: implications for vaccine design. Cancer Immunol Immunother 2019; 68:247-256. [PMID: 30406375 PMCID: PMC6394487 DOI: 10.1007/s00262-018-2266-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 10/19/2018] [Indexed: 01/08/2023]
Abstract
The oncofoetal antigen 5T4 is a promising T cell target in the context of colorectal cancer, as demonstrated by a recent clinical study where 5T4-specific T cell responses, induced by vaccination or cyclophosphamide, were associated with a significantly prolonged survival of patients with metastatic disease. Whilst Th1-type (IFN-γ+) responses specific to 5T4, and other oncofoetal antigens, are often readily detectable in early stage CRC patients and healthy donors, their activity is suppressed as the cancer progresses by CD4+CD25hiFoxp3+ regulatory T cells (Treg) which contribute to the immunosuppressive environment conducive to tumour growth. This study mapped the fine specificity of Th1 and Treg cell responses to the 5T4 protein. Surprisingly, both immunogenic peptides and those recognised by Tregs clustered in the same HLA-DR transcending epitope-rich hotspots within the 5T4 protein. Similarly, regions of low Th1-cell immunogenicity also did not contain peptides capable of stimulating Tregs, further supporting the notion that Treg and Th1 cells recognise the same peptides. Understanding the rules which govern the balance of Th1 and Treg cells responding to a given peptide specificity is, therefore, of fundamental importance to designing strategies for manipulating the balance in favour of Th1 cells, and thus the most effective anti-cancer T cell responses.
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Affiliation(s)
- Matthieu Besneux
- Division of Infection and Immunity, Henry Wellcome Building, Cardiff University, Health Park, Cardiff, CF14 4XN, UK
| | | | - Martin J Scurr
- Division of Infection and Immunity, Henry Wellcome Building, Cardiff University, Health Park, Cardiff, CF14 4XN, UK
| | - Bruce J MacLachlan
- Division of Infection and Immunity, Henry Wellcome Building, Cardiff University, Health Park, Cardiff, CF14 4XN, UK
| | - Adam Christian
- Department of Pathology, University Hospital of Wales, Cardiff, UK
| | - Michael M Davies
- Department of Colorectal Surgery, University Hospital of Wales, Cardiff, UK
| | - Rachel Hargest
- Department of Colorectal Surgery, University Hospital of Wales, Cardiff, UK
- CCMRC, Division of Cancer and Genetics, Henry Wellcome Building, Cardiff University, Cardiff, UK
| | - Simon Phillips
- Department of Colorectal Surgery, University Hospital of Wales, Cardiff, UK
| | - Andrew Godkin
- Division of Infection and Immunity, Henry Wellcome Building, Cardiff University, Health Park, Cardiff, CF14 4XN, UK.
- Department of Gastroenterology, Hepatology and Endoscopy, University Hospital of Wales, Cardiff, UK.
| | - Awen Gallimore
- Division of Infection and Immunity, Henry Wellcome Building, Cardiff University, Health Park, Cardiff, CF14 4XN, UK
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46
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Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis. Semin Cancer Biol 2019; 64:29-35. [PMID: 30716481 DOI: 10.1016/j.semcancer.2019.01.006] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 01/24/2019] [Accepted: 01/31/2019] [Indexed: 01/05/2023]
Abstract
Regulatory T-cells (Tregs) can facilitate immune evasion by tumor cells by dampening anti-tumor immunity. Reduced Teff/Treg ratio and enhanced Treg functional activity have been observed in patients suffering from different types of cancers, and attenuated Treg numbers/functions can serve as prognostic indicators. Normally, Tregs play an essential role in the maintenance of immune tolerance and prevention of autoimmunity. The most common immune checkpoint blockers (ICB) targeting co-inhibitory receptors such as anti-CTLA4 (ipilimumab and tremelimumab) and anti-PD1 (pembrolizumab and nivolumab)/anti-PD-L1 (atezolizumab) have achieved unprecedented success in cancer treatment by facilitating an effective anti-tumor immune response, at least in part, by blocking Treg mediated immunosuppression. While ICBs have shown remarkable success in cancer immunotherapy, immune-related adverse events (IRAEs) arising from ICB have forced consideration of ways to maintain immune homeostasis post ICB treatment. Preclinical models of IRAEs have shown a negative correlation between Treg numbers and IRAEs. Therefore, understanding the "ying-yang" role of Tregs in the regulation of autoimmunity and anti-tumor immunity is critical to provoking an effective anti-tumor response while maintaining immune homeostasis. Studies aimed at developing effective approaches to minimize IRAEs without compromising anti-tumor immunity are underway. Herein, we discuss 1) the critical role of key co-inhibitory receptors on Treg homeostasis and tumor tolerance; 2) how co-receptor blockade by cancer immunotherapy can lead to autoimmune adverse events; and 3) recently emerging management strategies to minimize autoimmune adverse events arising from ICB.
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47
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Moreira TG, Horta LS, Gomes-Santos AC, Oliveira RP, Queiroz NMGP, Mangani D, Daniel B, Vieira AT, Liu S, Rodrigues AM, Gomes DA, Gabriely G, Ferreira E, Weiner HL, Rezende RM, Nagy L, Faria AMC. CLA-supplemented diet accelerates experimental colorectal cancer by inducing TGF-β-producing macrophages and T cells. Mucosal Immunol 2019; 12:188-199. [PMID: 30279515 DOI: 10.1038/s41385-018-0090-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 08/24/2018] [Accepted: 09/07/2018] [Indexed: 02/07/2023]
Abstract
Conjugated linoleic acid (CLA) has been shown to activate the nuclear receptor PPAR-γ and modulate metabolic and immune functions. Despite the worldwide use of CLA dietary supplementation, strong scientific evidence for its proposed beneficial actions are missing. We found that CLA-supplemented diet reduced mucosal damage and inflammatory infiltrate in the dextran sodium sulfate (DSS)-induced colitis model. Conditional deletion of PPAR-γ in macrophages from mice supplemented with CLA diet resulted in loss of this protective effect of CLA, suggesting a PPAR-γ-dependent mechanism mediated by macrophages. However, CLA supplementation significantly worsened colorectal tumor formation induced by azoxymethane and DSS by inducing macrophage and T-cell-producing TGF-β via PPAR-γ activation. Accordingly, either macrophage-specific deletion of PPAR-γ or in vivo neutralization of latency-associated peptide (LAP, a membrane-bound TGF-β)-expressing cells abrogated the protumorigenic effect of CLA. Thus, the anti-inflammatory properties of CLA are associated with prevention of colitis but also with development of colorectal cancer.
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Affiliation(s)
- T G Moreira
- Departamento de Alimentos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Campus Pampulha, 31270-901, Belo Horizonte, MG, Brazil. .,Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. .,Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. .,Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
| | - L S Horta
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - A C Gomes-Santos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - R P Oliveira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - N M G P Queiroz
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - D Mangani
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - B Daniel
- Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.,Department of Medicine, School of Medicine, Johns Hopkins All Children's Hospital, Johns Hopkins University, St. Petersburg, FL, 33701, USA
| | - A T Vieira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - S Liu
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - A M Rodrigues
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - D A Gomes
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - G Gabriely
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - E Ferreira
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - H L Weiner
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - R M Rezende
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - L Nagy
- Diabetes and Obesity Research Center, Sanford Burnham Medical Research Institute, Lake Nona, Orlando, FL, USA.,Department of Medicine, School of Medicine, Johns Hopkins All Children's Hospital, Johns Hopkins University, St. Petersburg, FL, 33701, USA
| | - A M C Faria
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
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48
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CD39 + regulatory T cells accumulate in colon adenocarcinomas and display markers of increased suppressive function. Oncotarget 2018; 9:36993-37007. [PMID: 30651930 PMCID: PMC6319332 DOI: 10.18632/oncotarget.26435] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 11/26/2018] [Indexed: 12/21/2022] Open
Abstract
Increasing knowledge of the function and regulation of tumor-infiltrating lymphocytes has led to new insights in cancer immunotherapy. Regulatory T cells (Treg) accumulate in colon tumors, and we recently showed that CD39+ Treg from cancer patients inhibit transendothelial migration of conventional T cells. CD39 mediates the hydrolysis of ATP to immunosuppressive adenosine and adds to the immunosuppressive effects of Treg. Here, we further investigated the regulatory features of intratumoral CD39+ Treg in colon cancer. Using flow cytometry analyses of cells from 46 colon cancer patients, we confirm the accumulation of CD39+ Treg in the tumor tissue compared to unaffected colon tissue, and also show that tumor-infiltrating Treg express more CD39 and Foxp3 on a per cell basis. Furthermore, CD39+ Treg in tumors express markers indicating increased turnover and suppressive ability. In particular, tumor-infiltrating CD39+ Treg have high expression of surface molecules related to immunosuppression, such as ICOS, PD-L1 and CTLA-4. Functional suppression assays also indicate potent suppressive capacity of CD39+ Treg on proliferation and IFN-γ secretion by conventional T cells. In conclusion, our results identify tumor-infiltrating CD39+ Treg as a numerous and potentially important immunosuppressive subset, and suggest that immunotherapy aimed at reducing the activity of CD39+ Treg may be particularly useful in the setting of colon cancer.
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49
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Kumar P, Bhattacharya P, Prabhakar BS. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J Autoimmun 2018; 95:77-99. [PMID: 30174217 PMCID: PMC6289740 DOI: 10.1016/j.jaut.2018.08.007] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/22/2018] [Accepted: 08/26/2018] [Indexed: 12/22/2022]
Abstract
The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various co-stimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.
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Affiliation(s)
- Prabhakaran Kumar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA
| | - Palash Bhattacharya
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA; Department of Ophthalmology, Associate Dean for Technological Innovation and Training, University of Illinois College of Medicine, Room E-705, (M/C 790), 835 S. Wolcott Ave, Chicago, IL, 60612, USA.
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50
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The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases. Immunity 2018; 49:1004-1019. [DOI: 10.1016/j.immuni.2018.12.001] [Citation(s) in RCA: 153] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/25/2018] [Accepted: 11/30/2018] [Indexed: 12/14/2022]
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