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Brown ME, Thirawatananond P, Peters LD, Kern EJ, Vijay S, Sachs LK, Posgai AL, Brusko MA, Shapiro MR, Mathews CE, Bacher R, Brusko TM. Inhibition of CD226 co-stimulation suppresses diabetes development in the NOD mouse by augmenting regulatory T cells and diminishing effector T cell function. Diabetologia 2025; 68:397-418. [PMID: 39636437 PMCID: PMC11732877 DOI: 10.1007/s00125-024-06329-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/10/2024] [Indexed: 12/07/2024]
Abstract
AIMS/HYPOTHESIS Immunotherapeutics targeting T cells are crucial for inhibiting autoimmune disease progression proximal to disease onset in type 1 diabetes. There is an outstanding need to augment the durability and effectiveness of T cell targeting therapies by directly restraining proinflammatory T cell subsets, while simultaneously augmenting regulatory T cell (Treg) activity. Here, we present a novel strategy for preventing diabetes incidence in the NOD mouse model using a blocking monoclonal antibody targeting the type 1 diabetes risk-associated T cell co-stimulatory receptor, CD226. METHODS Female NOD mice were treated with anti-CD226 at 7-8 weeks of age and then monitored for diabetes incidence and therapeutic mechanism of action. RESULTS Compared with isotype-treated controls, anti-CD226-treated NOD mice showed reduced insulitis severity (0.84-fold, p=0.0002) at 12 weeks and decreased disease incidence (HR 0.41, p=0.015) at 30 weeks. Flow cytometric analysis performed 5 weeks post treatment demonstrated reduced proliferation of conventional CD4+ T cells (0.87-fold, p=0.030) and CD8+ (0.78-fold, p=0.0018) effector memory T cells in spleens of anti-CD226-treated mice. Phenotyping of pancreatic Tregs revealed increased CD25 expression (2.05-fold, p=0.0073) and signal transducer and activator of transcription 5 (STAT5) phosphorylation (1.39-fold, p=0.0007) following anti-CD226, with splenic Tregs displaying augmented suppression of CD4+ responder T cells (Tresps) (1.49-fold, p=0.0008, 1:2 Treg:Tresp) in vitro. Anti-CD226-treated mice exhibited reduced frequencies of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8+ T cells in the pancreas, using both ex vivo tetramer staining (0.50-fold, p=0.0317) and single-cell T cell receptor sequencing (0.61-fold, p=0.022) approaches. 51Cr-release assays demonstrated reduced cell-mediated lysis of beta cells (0.61-fold, p<0.0001, 1:1 effector:target) by anti-CD226-treated autoreactive cytotoxic T lymphocytes. CONCLUSIONS/INTERPRETATION CD226 blockade reduces T cell cytotoxicity and improves Treg function, representing a targeted and rational approach for restoring immune regulation in type 1 diabetes.
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MESH Headings
- Animals
- Mice, Inbred NOD
- Mice
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/drug effects
- Female
- Antigens, Differentiation, T-Lymphocyte/metabolism
- Antigens, Differentiation, T-Lymphocyte/immunology
- T Lineage-Specific Activation Antigen 1
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal/pharmacology
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Affiliation(s)
- Matthew E Brown
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Puchong Thirawatananond
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Leeana D Peters
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Elizabeth J Kern
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Sonali Vijay
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Lindsey K Sachs
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Amanda L Posgai
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Maigan A Brusko
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Melanie R Shapiro
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Clayton E Mathews
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Rhonda Bacher
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
- Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA
| | - Todd M Brusko
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
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Shi J, Pei X, Peng J, Wu C, Lv Y, Wang X, Zhou Y, Yuan X, Dong X, Zhou S, Xu D, Zhao J, Liu J, Huang J, Du B, Yao C, Zeng X, Li M, Chen H, Wang Q. Monocyte-macrophage dynamics as key in disparate lung and peripheral immune responses in severe anti-melanoma differentiation-associated gene 5-positive dermatomyositis-related interstitial lung disease. Clin Transl Med 2025; 15:e70226. [PMID: 39902678 PMCID: PMC11791760 DOI: 10.1002/ctm2.70226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/18/2025] [Accepted: 01/28/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM) is a rare inflammatory autoimmune disorder often complicated by life-threatening rapidly progressive interstitial lung disease (RP-ILD). The underlying mechanisms driving immune dysfunction and lung injury, however, remain poorly understood. The study aims to gain insights into the disrupted immune landscape in peripheral and pulmonary compartments of severe anti-MDA5+ DM and explore potential therapeutic targets. METHODS We employed single-cell RNA sequencing to examine cellular constituents within five patients' bronchoalveolar lavage fluid and paired peripheral blood mononuclear cells. Luminex assay and flow cytometry were further applied to validate the results. RESULTS Our analysis revealed starkly contrasting immune landscapes between the periphery and lungs, with peripheral immune suppression juxtaposed against pulmonary immune hyperactivation. Central to this dysregulation was the monocyte-macrophage lineage. Circulating monocytes exhibited an immunosuppressive phenotype, characterised by diminished cytokine production, reduced MHC II expression, and features resembling myeloid-derived suppressor cells. These monocytes were recruited to the lungs, where they differentiated into monocyte-derived alveolar macrophages (Mo-AMs) with robust proinflammatory and profibrotic activities. Mo-AMs drove cytokine storms and produced chemokines that amplified inflammatory cell recruitment and lung tissue remodelling. Additionally, peripheral T and NK cells exhibited increased cell death and active migration into the lungs, which may be the cause of lymphopenia. CONCLUSIONS Our study underscores the pivotal role of monocyte-macrophage dynamics in the immunopathogenesis of anti-MDA5+-associated RP-ILD, offering critical insights into compartment-specific immune dysregulation. These findings suggest potential therapeutic strategies targeting monocyte recruitment and macrophage activation to mitigate disease progression. KEY POINTS Peripheral immune suppression and pulmonary immune hyperactivation characterise the distinct immune landscapes in anti-MDA5+DM with RP-ILD. Circulating monocytes transition from an immunosuppressive phenotype in the periphery to proinflammatory and profibrotic Mo-AMs in the lungs. Chemokines produced by Mo-AMs drive monocyte and other immune cell recruitment to the lungs, amplifying pulmonary inflammation.
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Affiliation(s)
- Jia Shi
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Xiaoya Pei
- Department of Biochemistry and Molecular BiologyState Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jinmin Peng
- Medical Intensive Care UnitState Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical SciencesBeijingChina
| | - Chanyuan Wu
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Yulin Lv
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Xiaoman Wang
- Department of Biochemistry and Molecular BiologyState Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yangzhong Zhou
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Xueting Yuan
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Xingbei Dong
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Shuang Zhou
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Dong Xu
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Jiuliang Zhao
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Jun Liu
- State Key Laboratory of Protein and Plant Gene ResearchSchool of Life Sciences, Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
| | - Jiao Huang
- Department of RheumatologyAffiliated Hangzhou First People's HospitalWestlake University School of MedicineHangzhouChina
| | - Bin Du
- Medical Intensive Care UnitState Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical SciencesBeijingChina
| | - Chen Yao
- College of Pulmonary and Critical Care MedicineChinese PLA General HospitalBeijingChina
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID)Ministry of Science & TechnologyState Key Laboratory of Common Mechanism Research for Major DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Mengtao Li
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID), Ministry of Science & TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
| | - Houzao Chen
- Department of Biochemistry and Molecular BiologyState Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Qian Wang
- Department of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC‐DID)Ministry of Science & TechnologyState Key Laboratory of Common Mechanism Research for Major DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijingChina
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Hamlin RE, Pienkos SM, Chan L, Stabile MA, Pinedo K, Rao M, Grant P, Bonilla H, Holubar M, Singh U, Jacobson KB, Jagannathan P, Maldonado Y, Holmes SP, Subramanian A, Blish CA. Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution. Sci Transl Med 2024; 16:eadr1032. [PMID: 39536117 PMCID: PMC12148066 DOI: 10.1126/scitranslmed.adr1032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024]
Abstract
Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor-β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2-like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.
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Affiliation(s)
- Rebecca E. Hamlin
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Shaun M. Pienkos
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Leslie Chan
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mikayla A. Stabile
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Kassandra Pinedo
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mallika Rao
- Stanford Center for Clinical Research, Stanford University, Stanford, CA 94305, USA
| | - Philip Grant
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hector Bonilla
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Marisa Holubar
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Upinder Singh
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Karen B. Jacobson
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Kaiser Permanente Vaccine Study Center, Oakland, CA 94612, USA
| | - Prasanna Jagannathan
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Yvonne Maldonado
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Susan P. Holmes
- Department of Statistics, Stanford University, Stanford, CA 94305, USA
| | - Aruna Subramanian
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Catherine A. Blish
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA
- Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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4
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Chen S, Zhu H, Jounaidi Y. Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization. Signal Transduct Target Ther 2024; 9:302. [PMID: 39511139 PMCID: PMC11544004 DOI: 10.1038/s41392-024-02005-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 08/25/2024] [Accepted: 09/17/2024] [Indexed: 11/15/2024] Open
Abstract
Natural killer (NK) cells, initially identified for their rapid virus-infected and leukemia cell killing and tumor destruction, are pivotal in immunity. They exhibit multifaceted roles in cancer, viral infections, autoimmunity, pregnancy, wound healing, and more. Derived from a common lymphoid progenitor, they lack CD3, B-cell, or T-cell receptors but wield high cytotoxicity via perforin and granzymes. NK cells orchestrate immune responses, secreting inflammatory IFNγ or immunosuppressive TGFβ and IL-10. CD56dim and CD56bright NK cells execute cytotoxicity, while CD56bright cells also regulate immunity. However, beyond the CD56 dichotomy, detailed phenotypic diversity reveals many functional subsets that may not be optimal for cancer immunotherapy. In this review, we provide comprehensive and detailed snapshots of NK cells' functions and states of activation and inhibitions in cancer, autoimmunity, angiogenesis, wound healing, pregnancy and fertility, aging, and senescence mediated by complex signaling and ligand-receptor interactions, including the impact of the environment. As the use of engineered NK cells for cancer immunotherapy accelerates, often in the footsteps of T-cell-derived engineering, we examine the interactions of NK cells with other immune effectors and relevant signaling and the limitations in the tumor microenvironment, intending to understand how to enhance their cytolytic activities specifically for cancer immunotherapy.
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Affiliation(s)
- Sumei Chen
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China.
| | - Haitao Zhu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Youssef Jounaidi
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Lopez M, Crompot E, Josselin E, Farina A, Rubis M, Castellano R, Fares J, Wehbe M, Collette Y, Charafe E, Blanchin S, Romagne F, Pálfi A, Hechler T, Pahl A, Azim HA, Lhospice F, Mamessier E, Bertucci F, Elands J, Préville X, Olive D. ETx-22, a Novel Nectin-4-Directed Antibody-Drug Conjugate, Demonstrates Safety and Potent Antitumor Activity in Low-Nectin-4-Expressing Tumors. CANCER RESEARCH COMMUNICATIONS 2024; 4:2998-3012. [PMID: 39440991 PMCID: PMC11583010 DOI: 10.1158/2767-9764.crc-24-0176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 07/13/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
SIGNIFICANCE ETx-22, a novel ADC combining a tumor nectin-4-specific antibody and an innovative linker to exatecan, demonstrates significant and durable responses in low-target-expressing tumor models that are resistant to MMAE-based EV and has a better toxicity profile. This new ADC has the potential to benefit additional patient populations beyond its current indication.
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Affiliation(s)
- Marc Lopez
- Laboratoire d’Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix-Marseille Université U105, Institut Paoli-Calmettes, Label “Ligue Contre le Cancer”, Marseille, France
| | - Emerence Crompot
- Laboratoire d’Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix-Marseille Université U105, Institut Paoli-Calmettes, Label “Ligue Contre le Cancer”, Marseille, France
| | - Emmanuelle Josselin
- TrGET Platform, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli-Calmettes, Marseille, France
| | - Anne Farina
- ICEP Platform, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli-Calmettes, Marseille, France
| | - Marion Rubis
- ICEP Platform, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli-Calmettes, Marseille, France
| | - Remy Castellano
- TrGET Platform, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli-Calmettes, Marseille, France
| | - Joanna Fares
- Emergence Therapeutics SA, A Wholly Owned Subsidiary of Eli Lilly and Company, Marseille, France
| | - Maria Wehbe
- Emergence Therapeutics SA, A Wholly Owned Subsidiary of Eli Lilly and Company, Marseille, France
| | - Yves Collette
- TrGET Platform, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli-Calmettes, Marseille, France
| | - Emmanuelle Charafe
- ICEP Platform, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli-Calmettes, Marseille, France
| | | | | | | | | | | | - Hatem A. Azim
- Emergence Therapeutics SA, A Wholly Owned Subsidiary of Eli Lilly and Company, Marseille, France
| | - Florence Lhospice
- Emergence Therapeutics SA, A Wholly Owned Subsidiary of Eli Lilly and Company, Marseille, France
| | - Emilie Mamessier
- Laboratoire d’Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix-Marseille Université U105, Institut Paoli-Calmettes, Label “Ligue Contre le Cancer”, Marseille, France
| | - François Bertucci
- Laboratoire d’Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix-Marseille Université U105, Institut Paoli-Calmettes, Label “Ligue Contre le Cancer”, Marseille, France
- Département d’Oncologie Médicale, Institut Paoli-Calmettes Marseille, France
| | - Jack Elands
- Emergence Therapeutics SA, A Wholly Owned Subsidiary of Eli Lilly and Company, Marseille, France
| | - Xavier Préville
- Emergence Therapeutics SA, A Wholly Owned Subsidiary of Eli Lilly and Company, Marseille, France
| | - Daniel Olive
- Equipe Immunité et Cancer, Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix-Marseille Université U105, Institut Paoli-Calmettes, Marseille, France
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6
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Bennstein SB, Uhrberg M. Circulating innate lymphoid cells (cILCs): Unconventional lymphocytes with hidden talents. J Allergy Clin Immunol 2024; 154:523-536. [PMID: 39046403 DOI: 10.1016/j.jaci.2024.06.016] [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: 03/18/2024] [Revised: 05/16/2024] [Accepted: 06/28/2024] [Indexed: 07/25/2024]
Abstract
Innate lymphoid cells (ILCs) are a group of lymphocytes that are devoid of antigen-specific receptors and are mainly found in tissues. The subtypes ILC1, 2, and 3 mirror T-cell functionality in terms of cytokine production and expression of key transcription factors. Although the majority of ILCs are found in tissue (tILCs), they have also been described within the circulation (cILCs). As a result of their better accessibility and putative prognostic value, human cILCs are getting more and more attention in clinical research. However, cILCs are in many aspects functionally distinct from their tILC counterparts. In fact, from the 3 ILC subsets found within the circulation, only for cILC2s could a clear functional correspondence to their tissue counterparts be established. Indeed, cILC2s are emerging as a major driver of allergic reactions with a particular role in asthma. In contrast, recent studies revealed that cILC1s and cILC3s are predominantly in an immature state and constitute progenitors for natural killer cells and ILCs, respectively. We provide an overview about the phenotype and function of the different cILC subtypes compared to tILCs in health and disease, including transcriptomic signatures, frequency dynamics, and potential clinical value. Furthermore, we will highlight the dynamics of the NKp44+ ILC3 subset, which emerges as prognostic marker in peripheral blood for inflammatory bowel disease and leukemia.
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Affiliation(s)
- Sabrina B Bennstein
- Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
| | - Markus Uhrberg
- Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
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7
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Jeong JY, Bafor AE, Freeman BH, Chen PR, Park ES, Kim E. Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition. Biomedicines 2024; 12:1795. [PMID: 39200259 PMCID: PMC11351371 DOI: 10.3390/biomedicines12081795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 09/02/2024] Open
Abstract
Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT).
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Affiliation(s)
| | | | | | | | | | - Eunhee Kim
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (J.Y.J.); (A.E.B.); (B.H.F.); (P.R.C.); (E.S.P.)
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8
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Brown ME, Thirawatananond P, Peters LD, Kern EJ, Vijay S, Sachs LK, Posgai AL, Brusko MA, Shapiro MR, Mathews CE, Bacher R, Brusko TM. Inhibition of CD226 Co-Stimulation Suppresses Diabetes Development in the NOD Mouse by Augmenting Tregs and Diminishing Effector T Cell Function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.16.603756. [PMID: 39071293 PMCID: PMC11275941 DOI: 10.1101/2024.07.16.603756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Aims/hypothesis Immunotherapeutics targeting T cells are crucial for inhibiting autoimmune disease progression proximal to disease onset in type 1 diabetes. A growing number of T cell-directed therapeutics have demonstrated partial therapeutic efficacy, with anti-CD3 (α-CD3) representing the only regulatory agency-approved drug capable of slowing disease progression through a mechanism involving the induction of partial T cell exhaustion. There is an outstanding need to augment the durability and effectiveness of T cell targeting by directly restraining proinflammatory T helper type 1 (Th1) and type 1 cytotoxic CD8+ T cell (Tc1) subsets, while simultaneously augmenting regulatory T cell (Treg) activity. Here, we present a novel strategy for reducing diabetes incidence in the NOD mouse model using a blocking monoclonal antibody targeting the type 1 diabetes-risk associated T cell co-stimulatory receptor, CD226. Methods Female NOD mice were treated with anti-CD226 between 7-8 weeks of age and then monitored for diabetes incidence and therapeutic mechanism of action. Results Compared to isotype-treated controls, anti-CD226 treated NOD mice showed reduced insulitis severity at 12 weeks and decreased disease incidence at 30 weeks. Flow cytometric analysis performed five weeks post-treatment demonstrated reduced proliferation of CD4+ and CD8+ effector memory T cells in spleens of anti-CD226 treated mice. Phenotyping of pancreatic Tregs revealed increased CD25 expression and STAT5 phosphorylation following anti-CD226, with splenic Tregs displaying augmented suppression of CD4+ T cell responders in vitro. Anti-CD226 treated mice exhibited reduced frequencies of islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP)-reactive CD8+ T cells in the pancreas, using both ex vivo tetramer staining and single-cell T cell receptor sequencing (scTCR-seq) approaches. 51Cr-release assays demonstrated reduced cell-mediated lysis of beta-cells by anti-CD226-treated autoreactive cytotoxic T lymphocytes. Conclusions/interpretation CD226 blockade reduces T cell cytotoxicity and improves Treg function, representing a targeted and rational approach for restoring immune regulation in type 1 diabetes.
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Affiliation(s)
- Matthew E. Brown
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Puchong Thirawatananond
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Leeana D. Peters
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Elizabeth J. Kern
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Sonali Vijay
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Lindsey K. Sachs
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Amanda L. Posgai
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Maigan A. Brusko
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Melanie R. Shapiro
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Clayton E. Mathews
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Rhonda Bacher
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32610
| | - Todd M. Brusko
- Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610
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9
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Hu S, Han P, Wang M, Cao X, Liu H, Zhang S, Zhang S, Liu J, Han Y, Xiao J, Chen Q, Miao K, Qi J, Tan S, Gao GF, Wang H. Structural basis for the immune recognition and selectivity of the immune receptor PVRIG for ligand Nectin-2. Structure 2024; 32:918-929.e4. [PMID: 38626767 DOI: 10.1016/j.str.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/27/2024] [Accepted: 03/20/2024] [Indexed: 06/27/2024]
Abstract
Nectin and nectin-like (Necl) co-receptor axis, comprised of receptors DNAM-1, TIGIT, CD96, PVRIG, and nectin/Necl ligands, is gaining prominence in immuno-oncology. Within this axis, the inhibitory receptor PVRIG recognizes Nectin-2 with high affinity, but the underlying molecular basis remains unknown. By determining the crystal structure of PVRIG in complex with Nectin-2, we identified a unique CC' loop in PVRIG, which complements the double-lock-and-key binding mode and contributes to its high affinity for Nectin-2. The association of the corresponding charged residues in the F-strands explains the ligand selectivity of PVRIG toward Nectin-2 but not for Necl-5. Moreover, comprehensive comparisons of the binding capacities between co-receptors and ligands provide innovative insights into the intra-axis immunoregulatory mechanism. Taken together, these findings broaden our understanding of immune recognition and regulation mediated by nectin/Necl co-receptors and provide a rationale for the development of immunotherapeutic strategies targeting the nectin/Necl axis.
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Affiliation(s)
- Songtao Hu
- Institutes of Physical Science and Information Technology, Anhui University, Anhui 230601, China; Cancer Center, Faculty of Health Sciences, University of Macau, Taipa Macau SAR, China; Beijing Life Science Academy, Beijing 102200, China
| | - Pu Han
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
| | - Meiyu Wang
- Institutes of Physical Science and Information Technology, Anhui University, Anhui 230601, China
| | - Xiaoqing Cao
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101125, China
| | - Hao Liu
- Cancer Center, Faculty of Health Sciences, University of Macau, Taipa Macau SAR, China
| | - Shuailong Zhang
- Institutes of Physical Science and Information Technology, Anhui University, Anhui 230601, China
| | - Shuijun Zhang
- College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Jun Liu
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China
| | - Yi Han
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101125, China
| | - Jinhe Xiao
- Department of Prevention and Treatment of Breast Disease, Haidian District Maternal and Child Health Care Hospital, Beijing 100080, China
| | - Qiang Chen
- Cancer Center, Faculty of Health Sciences, University of Macau, Taipa Macau SAR, China
| | - Kai Miao
- Cancer Center, Faculty of Health Sciences, University of Macau, Taipa Macau SAR, China
| | - Jianxun Qi
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
| | - Shuguang Tan
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
| | - George Fu Gao
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
| | - Han Wang
- Beijing Life Science Academy, Beijing 102200, China; Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100080, China.
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10
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Song Y, Wang Y, Li J, Shen Y, Hou Y, Fu Z, Fang L, Jin B, Chen L. CD226 promotes renal fibrosis by regulating macrophage activation and migration. J Leukoc Biol 2024; 116:103-117. [PMID: 38660893 DOI: 10.1093/jleuko/qiae054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 01/29/2024] [Accepted: 02/21/2024] [Indexed: 04/26/2024] Open
Abstract
It has been found that CD226 plays an important role in regulating macrophage function, but its expression and function in macrophages during renal fibrogenesis have not been studied. Our data demonstrated that CD226 expression in macrophages was obviously upregulated in the unilateral ureteral obstruction model, while CD226 deficiency attenuated collagen deposition in renal interstitium along with fewer M1 within renal cortex and renal medulla and a lower level of proinflammatory factors compared to that of control littermates. Further studies demonstrated that Cd226-/- bone marrow-derived macrophages transferring could significantly reduce the tubular injury, collagen deposition, and proinflammatory cytokine secretion compared with that of Cd226+/+ bone marrow-derived macrophages transferring in the unilateral ureteral obstruction model. Mechanistic investigations revealed that CD226 promoted proinflammatory M1 macrophage accumulation in the kidney via suppressing KLF4 expression in macrophages. Therefore, our results uncovered a pathogenic role of CD226 during the development of chronic kidney disease by promoting monocyte infiltration from peripheral blood into the kidney and enhancing macrophage activation toward the inflammatory phenotype by suppressing KLF4 expression.
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Affiliation(s)
- Yun Song
- Department of Immunology, Air Force Medical University, No.169, Changle West Road, Xincheng District, Xi'an 710032, ShaanXi, China
| | - Yazhen Wang
- Department of Immunology, Air Force Medical University, No.169, Changle West Road, Xincheng District, Xi'an 710032, ShaanXi, China
| | - Juan Li
- College of Life Sciences, Northwest University, No.229, Taibai North Road, Beilin District, Xi'an 710069, ShaanXi, China
| | - Yuting Shen
- Department of Immunology, Air Force Medical University, No.169, Changle West Road, Xincheng District, Xi'an 710032, ShaanXi, China
| | - Yongli Hou
- Department of Immunology, Air Force Medical University, No.169, Changle West Road, Xincheng District, Xi'an 710032, ShaanXi, China
| | - Zhaoyue Fu
- Department of Immunology, Air Force Medical University, No.169, Changle West Road, Xincheng District, Xi'an 710032, ShaanXi, China
| | - Liang Fang
- Department of Immunology, Air Force Medical University, No.169, Changle West Road, Xincheng District, Xi'an 710032, ShaanXi, China
| | - Boquan Jin
- Department of Immunology, Air Force Medical University, No.169, Changle West Road, Xincheng District, Xi'an 710032, ShaanXi, China
| | - Lihua Chen
- Department of Immunology, Air Force Medical University, No.169, Changle West Road, Xincheng District, Xi'an 710032, ShaanXi, China
- College of Life Sciences, Northwest University, No.229, Taibai North Road, Beilin District, Xi'an 710069, ShaanXi, China
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11
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Hamlin RE, Pienkos SM, Chan L, Stabile MA, Pinedo K, Rao M, Grant P, Bonilla H, Holubar M, Singh U, Jacobson KB, Jagannathan P, Maldonado Y, Holmes SP, Subramanian A, Blish CA. Sex differences and immune correlates of Long COVID development, persistence, and resolution. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.18.599612. [PMID: 38948732 PMCID: PMC11212991 DOI: 10.1101/2024.06.18.599612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Sex differences have been observed in acute COVID-19 and Long COVID (LC) outcomes, with greater disease severity and mortality during acute infection in males and a greater proportion of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to the pathogenesis of LC. To investigate the immunologic underpinnings of LC development and persistence, we used single-cell transcriptomics, single-cell proteomics, and plasma proteomics on blood samples obtained during acute SARS-CoV-2 infection and at 3 and 12 months post-infection in a cohort of 45 patients who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Specifically, males who would develop LC at 3 months had widespread increases in TGF-β signaling during acute infection in proliferating NK cells. Females who would develop LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, and increased IL1 signaling in monocytes at 12 months post infection. Several immune features of LC were also conserved across sexes. Both males and females with LC had reduced co-stimulatory signaling from monocytes and broad upregulation of NF-κB transcription factors. In both sexes, those with persistent LC demonstrated increased LAG3, a marker of T cell exhaustion, reduced ETS1 transcription factor expression across lymphocyte subsets, and elevated intracellular IL-4 levels in T cell subsets, suggesting that ETS1 alterations may drive an aberrantly elevated Th2-like response in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.
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Affiliation(s)
- Rebecca E. Hamlin
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Shaun M. Pienkos
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Leslie Chan
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
- Stanford Immunology Program, Stanford University School of Medicine; Stanford, CA, USA
| | - Mikayla A. Stabile
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Kassandra Pinedo
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Mallika Rao
- Stanford Center for Clinical Research, Stanford University; Stanford, CA, USA
| | - Philip Grant
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Hector Bonilla
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Marisa Holubar
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Upinder Singh
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine; Stanford, CA, USA
| | - Karen B. Jacobson
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Prasanna Jagannathan
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine; Stanford, CA, USA
| | - Yvonne Maldonado
- Department of Pediatrics, Stanford University School of Medicine; Stanford, CA, USA
| | - Susan P. Holmes
- Department of Statistics, Stanford University; Stanford, CA, USA
| | - Aruna Subramanian
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Catherine A. Blish
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
- Stanford Medical Scientist Training Program, Stanford University School of Medicine; Stanford, CA, USA
- Chan Zuckerberg Biohub; San Francisco, CA, USA
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12
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Lan W, Li J, Ye Z, Liu Y, Luo S, Lu X, Cao Z, Chen Y, Chen H, Li Z. A subset of megakaryocytes regulates development of hematopoietic stem cell precursors. EMBO J 2024; 43:1722-1739. [PMID: 38580775 PMCID: PMC11065989 DOI: 10.1038/s44318-024-00079-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 02/26/2024] [Accepted: 02/28/2024] [Indexed: 04/07/2024] Open
Abstract
Understanding the regulatory mechanisms facilitating hematopoietic stem cell (HSC) specification during embryogenesis is important for the generation of HSCs in vitro. Megakaryocyte emerged from the yolk sac and produce platelets, which are involved in multiple biological processes, such as preventing hemorrhage. However, whether megakaryocytes regulate HSC development in the embryonic aorta-gonad-mesonephros (AGM) region is unclear. Here, we use platelet factor 4 (PF4)-Cre;Rosa-tdTomato+ cells to report presence of megakaryocytes in the HSC developmental niche. Further, we use the PF4-Cre;Rosa-DTA (DTA) depletion model to reveal that megakaryocytes control HSC specification in the mouse embryos. Megakaryocyte deficiency blocks the generation and maturation of pre-HSCs and alters HSC activity at the AGM. Furthermore, megakaryocytes promote endothelial-to-hematopoietic transition in a OP9-DL1 coculture system. Single-cell RNA-sequencing identifies megakaryocytes positive for the cell surface marker CD226 as the subpopulation with highest potential in promoting the hemogenic fate of endothelial cells by secreting TNFSF14. In line, TNFSF14 treatment rescues hematopoietic cell function in megakaryocyte-depleted cocultures. Taken together, megakaryocytes promote production and maturation of pre-HSCs, acting as a critical microenvironmental control factor during embryonic hematopoiesis.
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Affiliation(s)
- Wenlang Lan
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jinping Li
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zehua Ye
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yumin Liu
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Sifan Luo
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xun Lu
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhan Cao
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yifan Chen
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Hongtian Chen
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhuan Li
- Key Laboratory of Functional Proteomics of Guangdong Province, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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13
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Haghayegh Jahromi N, Gkountidi AO, Collado-Diaz V, Blatter K, Bauer A, Zambounis L, Medina-Sanchez JD, Russo E, Runge P, Restivo G, Gousopoulos E, Lindenblatt N, Levesque MP, Halin C. CD112 Supports Lymphatic Migration of Human Dermal Dendritic Cells. Cells 2024; 13:424. [PMID: 38474388 PMCID: PMC10931060 DOI: 10.3390/cells13050424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/02/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
Dendritic cell (DC) migration from peripheral tissues via afferent lymphatic vessels to draining lymph nodes (dLNs) is important for the organism's immune regulation and immune protection. Several lymphatic endothelial cell (LEC)-expressed adhesion molecules have thus far been found to support transmigration and movement within the lymphatic vasculature. In this study, we investigated the contribution of CD112, an adhesion molecule that we recently found to be highly expressed in murine LECs, to this process. Performing in vitro assays in the murine system, we found that transmigration of bone marrow-derived dendritic cells (BM-DCs) across or adhesion to murine LEC monolayers was reduced when CD112 was absent on LECs, DCs, or both cell types, suggesting the involvement of homophilic CD112-CD112 interactions. While CD112 was highly expressed in murine dermal LECs, CD112 levels were low in endogenous murine dermal DCs and BM-DCs. This might explain why we observed no defect in the in vivo lymphatic migration of adoptively transferred BM-DCs or endogenous DCs from the skin to dLNs. Compared to murine DCs, human monocyte-derived DCs expressed higher CD112 levels, and their migration across human CD112-expressing LECs was significantly reduced upon CD112 blockade. CD112 expression was also readily detected in endogenous human dermal DCs and LECs by flow cytometry and immunofluorescence. Upon incubating human skin punch biopsies in the presence of CD112-blocking antibodies, DC emigration from the tissue into the culture medium was significantly reduced, indicating impaired lymphatic migration. Overall, our data reveal a contribution of CD112 to human DC migration.
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Affiliation(s)
- Neda Haghayegh Jahromi
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Anastasia-Olga Gkountidi
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Victor Collado-Diaz
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Katharina Blatter
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Aline Bauer
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Lito Zambounis
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Jessica Danielly Medina-Sanchez
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Erica Russo
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Peter Runge
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
| | - Gaetana Restivo
- Department of Dermatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; (G.R.); (M.P.L.)
| | - Epameinondas Gousopoulos
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland; (E.G.); (N.L.)
| | - Nicole Lindenblatt
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland; (E.G.); (N.L.)
| | - Mitchell P. Levesque
- Department of Dermatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; (G.R.); (M.P.L.)
| | - Cornelia Halin
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland; (N.H.J.); (A.-O.G.); (V.C.-D.); (K.B.); (L.Z.); (J.D.M.-S.); (E.R.); (P.R.)
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14
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Perrone C, Bozzano F, Dal Bello MG, Del Zotto G, Antonini F, Munari E, Maggi E, Moretta F, Farshchi AH, Pariscenti G, Tagliamento M, Genova C, Moretta L, De Maria A. CD34 +DNAM-1 brightCXCR4 + haemopoietic precursors circulate after chemotherapy, seed lung tissue and generate functional innate-like T cells and NK cells. Front Immunol 2024; 15:1332781. [PMID: 38390333 PMCID: PMC10881815 DOI: 10.3389/fimmu.2024.1332781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 01/17/2024] [Indexed: 02/24/2024] Open
Abstract
Background There is little information on the trajectory and developmental fate of Lin-CD34+DNAM-1bright CXCR4+ progenitors exiting bone marrow during systemic inflammation. Objective To study Lin-CD34+DNAM-1bright CXCR4+ cell circulation in cancer patients, to characterize their entry into involved lung tissue and to characterize their progenies. Methods Flow cytometric analysis of PBMC from 18 patients with lung cancer on samples collected immediately before the first and the second treatment was performed to study Lin-CD34+DNAM-1bright CXCR4+ precursors. Precursors were purified (>99%) and cultured in vitro from all patients. Paired PBMC and tissue samples from patients undergoing tumor resection were analyzed by flow cytometry to assess tissue entry and compare phenotype and developmental potential of Lin-CD34+DNAM-1bright CXCR4+ cells in both compartments. Results Significant circulation of Lin-CD34+DNAM-1bright CXCR4+ precursors was observed 20d after the first treatment. Precursors express CXC3CR1, CXCR3, CXCR1 consistent with travel towards inflamed tissues. Flowcytometric analysis of lung tissue samples showed precursor presence in all patients in tumor and neighboring uninvolved areas. Successful purification and in vitro culture from both blood and lung tissue generates a minor proportion of maturing NK cells (<10%) and a predominant proportion (>85%) of α/β T-progenies with innate-like phenotype expressing NKG2D,NKp30,DNAM-1. Innate-like maturing T-cells in vitro are cytotoxic, can be triggered via NKR/TCR co-stimulation and display broad spectrum Th1,Th2 and Th1/Th17 cytokine production. Conclusion In advanced stage lung cancer CD34+DNAM-1brightCXCR4+ inflammatory precursors increase upon treatment, enter involved tissues, generate functional progenies and may thus represent an additional player contributing to immune balance in the highly SDF-1/CXCR4-biased pro-metastatic tumor microenvironment.
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Affiliation(s)
- Carola Perrone
- Experimental Immunology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Federica Bozzano
- Laboratorio Diagnostico di Autoimmunologia, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | | | - Genny Del Zotto
- Integrated Department of Services and Laboratories, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Francesca Antonini
- Integrated Department of Services and Laboratories, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Enrico Munari
- Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Enrico Maggi
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Francesca Moretta
- Department of Laboratory Medicine, Istituto di Ricovero e Cura a Carattere Scientifico Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy
| | | | - Gianluca Pariscenti
- Thoracic Surgery Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Marco Tagliamento
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, Genova, Italy
| | - Carlo Genova
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, Genova, Italy
| | - Lorenzo Moretta
- Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Andrea De Maria
- Department of Health Sciences, University of Genova, Genova, Italy
- Infections of Immunocompromised Hosts Unit, Division of Infectious Diseases, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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15
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Zhang P, Liu X, Gu Z, Jiang Z, Zhao S, Song Y, Yu J. Targeting TIGIT for cancer immunotherapy: recent advances and future directions. Biomark Res 2024; 12:7. [PMID: 38229100 PMCID: PMC10790541 DOI: 10.1186/s40364-023-00543-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 11/08/2023] [Indexed: 01/18/2024] Open
Abstract
As a newly identified checkpoint, T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is highly expressed on CD4+ T cells, CD8+ T cells, natural killer (NK) cells, regulatory T cells (Tregs), and tumor-infiltrating lymphocytes (TILs). TIGIT has been associated with NK cell exhaustion in vivo and in individuals with various cancers. It not only modulates NK cell survival but also mediates T cell exhaustion. As the primary ligand of TIGIT in humans, CD155 may be the main target for immunotherapy due to its interaction with TIGIT. It has been found that the anti-programmed cell death protein 1 (PD-1) treatment response in cancer immunotherapy is correlated with CD155 but not TIGIT. Anti-TIGIT alone and in combination with anti-PD-1 agents have been tested for cancer immunotherapy. Although two clinical studies on advanced lung cancer had positive results, the TIGIT-targeted antibody, tiragolumab, recently failed in two new trials. In this review, we highlight the current developments on TIGIT for cancer immunotherapy and discuss the characteristics and functions of TIGIT.
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Affiliation(s)
- Peng Zhang
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Thoracic Oncology, Zhengzhou, 450052, Henan, China
| | - Xinyuan Liu
- Institute of Biomedical Informatics, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Zhuoyu Gu
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Thoracic Oncology, Zhengzhou, 450052, Henan, China
| | - Zhongxing Jiang
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Song Zhao
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Yongping Song
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Jifeng Yu
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Henan International Joint Laboratory of Nuclear Protein Gene Regulation, Henan University College of Medicine, Kaifeng, 475004, Henan, China.
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16
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Jiang HX, Wang XD, Wang HX, Liu T. Baicalin attenuates pulmonary vascular remodeling by inhibiting calpain-1 mediated endothelial-to-mesenchymal transition. Heliyon 2023; 9:e23076. [PMID: 38144352 PMCID: PMC10746466 DOI: 10.1016/j.heliyon.2023.e23076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/26/2023] Open
Abstract
BACKGROUND Previous studies have demonstrated the beneficial effect of baicalin on pulmonary arterial hypertension (PAH), but the mechanism is unclear. AIM The aim of the present study was to evaluate the effect of baicalin on pulmonary vascular remodeling (PVR) with a focus on calpain-1-mediated endothelial-to-mesenchymal transition (EndMT). METHODS PAH was induced by intraperitoneal injection of monocrotaline (MCT) in rats and hypoxia in calpain-1 gene knockout (Capn1-/-) and wild-type C57BL/6 mice. An in vitro PVR model was established in PASMCs and HPAECs. RESULTS The data showed that baicalin treatment and calpain-1 inhibition alleviated MCT and hypoxia-induced increases in right ventricular systolic pressure (RVSP), prevented right ventricle hypertrophy and PVR, and attenuated cardiopulmonary fibrosis. Moreover, baicalin ameliorated PAH-induced EndMT, as evidenced by the suppressed expression of mesenchymal markers vimentin, and α-SMA and restored expression of endothelial markers CD31, and VE-cadherin. In vitro studies showed that baicalin treatment blocked TGF-β1-induced EndMT in HPAECs and abolished hypoxia-induced PASMC proliferation and migration. All the beneficial effects of baicalin on PVR in vitro and in vivo were accompanied by suppressed calpain-1 expression. Further study demonstrated that baicalin treatment and calpain-1 inhibition inhibited the enhanced expression of PI3K and p-AKT both in vitro and in vivo. CONCLUSIONS In conclusion, baicalin treatment attenuates PVR by inhibiting calpain-1 and PI3K/Akt-mediated EndMT.
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Affiliation(s)
- He-xi Jiang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Xiao-di Wang
- Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, 121001, China
| | - Hong-xin Wang
- Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou, 121000, China
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, China
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17
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Thirawatananond P, Brown ME, Sachs LK, Arnoletti JM, Yeh WI, Posgai AL, Shapiro MR, Chen YG, Brusko TM. Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability. Diabetes 2023; 72:1629-1640. [PMID: 37625150 PMCID: PMC10588280 DOI: 10.2337/db23-0307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/21/2023] [Indexed: 08/27/2023]
Abstract
Costimulation serves as a critical checkpoint for T-cell activation, and several genetic variants affecting costimulatory pathways confer risk for autoimmune diseases. A single nucleotide polymorphism (rs763361) in the CD226 gene encoding a costimulatory receptor increases susceptibility to multiple autoimmune diseases, including type 1 diabetes. We previously found that Cd226 knockout protected NOD mice from disease, but the impact of CD226 on individual immune subsets remained unclear. Our prior reports implicate regulatory T cells (Tregs), as human CD226+ Tregs exhibit reduced suppressive function. Hence, we hypothesized that genomic Cd226 gene deletion would increase Treg stability and that Treg-specific Cd226 deletion would inhibit diabetes in NOD mice. Indeed, crossing NOD.Cd226-/- and a NOD Treg-lineage tracing strain resulted in decreased pancreatic Foxp3-deficient "ex-Tregs." We generated a novel Treg-conditional knockout (TregΔCd226) strain that displayed decreased insulitis and diabetes incidence. CD226-deficient pancreatic Tregs had increased expression of the coinhibitory counter-receptor T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT). Moreover, NOD splenocytes treated with TIGIT-Fc fusion protein exhibited reduced T-cell proliferation and interferon-γ production following anti-CD3/CD28 stimulation. This study demonstrates that a CD226/TIGIT imbalance contributes to Treg instability in NOD mice and highlights the potential for therapeutic targeting this costimulatory pathway to halt autoimmunity. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Puchong Thirawatananond
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Matthew E. Brown
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Lindsey K. Sachs
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Juan M. Arnoletti
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Wen-I Yeh
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Amanda L. Posgai
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Melanie R. Shapiro
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
| | - Yi-Guang Chen
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
| | - Todd M. Brusko
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
- Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL
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18
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Arbaizar-Rovirosa M, Gallizioli M, Lozano JJ, Sidorova J, Pedragosa J, Figuerola S, Chaparro-Cabanillas N, Boya P, Graupera M, Claret M, Urra X, Planas AM. Transcriptomics and translatomics identify a robust inflammatory gene signature in brain endothelial cells after ischemic stroke. J Neuroinflammation 2023; 20:207. [PMID: 37691115 PMCID: PMC10494365 DOI: 10.1186/s12974-023-02888-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/31/2023] [Indexed: 09/12/2023] Open
Abstract
Vascular endothelial function is challenged during cerebral ischemia and reperfusion. The endothelial responses are involved in inflammatory leukocyte attraction, adhesion and infiltration, blood-brain barrier leakage, and angiogenesis. This study investigated gene expression changes in brain endothelial cells after acute ischemic stroke using transcriptomics and translatomics. We isolated brain endothelial mRNA by: (i) translating ribosome affinity purification, enabling immunoprecipitation of brain endothelial ribosome-attached mRNA for translatome sequencing and (ii) isolating CD31+ endothelial cells by fluorescence-activating cell sorting for classical transcriptomic analysis. Both techniques revealed similar pathways regulated by ischemia but they showed specific differences in some transcripts derived from non-endothelial cells. We defined a gene set characterizing the endothelial response to acute stroke (24h) by selecting the differentially expressed genes common to both techniques, thus corresponding with the translatome and minimizing non-endothelial mRNA contamination. Enriched pathways were related to inflammation and immunoregulation, angiogenesis, extracellular matrix, oxidative stress, and lipid trafficking and storage. We validated, by flow cytometry and immunofluorescence, the protein expression of several genes encoding cell surface proteins. The inflammatory response was associated with the endothelial upregulation of genes related to lipid storage functions and we identified lipid droplet biogenesis in the endothelial cells after ischemia. The study reports a robust translatomic signature of brain endothelial cells after acute stroke and identifies enrichment in novel pathways involved in membrane signaling and lipid storage. Altogether these results highlight the endothelial contribution to the inflammatory response, and identify novel molecules that could be targets to improve vascular function after ischemic stroke.
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Affiliation(s)
- Maria Arbaizar-Rovirosa
- Department of Neuroscience and Experimental Therapeutics, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036, Barcelona, Spain
- Cerebrovascular Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Mattia Gallizioli
- Department of Neuroscience and Experimental Therapeutics, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036, Barcelona, Spain
- Cerebrovascular Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan J Lozano
- Bioinformatics Platform, Centro de Investigación Biomédica en Red Enfermedades Hepáticas Y Digestivas (CIBEREHD), Barcelona, Spain
| | - Julia Sidorova
- Bioinformatics Platform, Centro de Investigación Biomédica en Red Enfermedades Hepáticas Y Digestivas (CIBEREHD), Barcelona, Spain
| | - Jordi Pedragosa
- Department of Neuroscience and Experimental Therapeutics, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036, Barcelona, Spain
- Cerebrovascular Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Sara Figuerola
- Department of Neuroscience and Experimental Therapeutics, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036, Barcelona, Spain
- Cerebrovascular Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Nerea Chaparro-Cabanillas
- Department of Neuroscience and Experimental Therapeutics, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036, Barcelona, Spain
- Cerebrovascular Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Patricia Boya
- Department of Neuroscience and Movement Science, University of Friburg, Fribourg, Switzerland
| | - Mariona Graupera
- Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Marc Claret
- Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
- Unitat Funcional de Patología Vascular Cerebral, Hospital Clínic, Barcelona, Spain
| | - Xabier Urra
- Cerebrovascular Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
- Unitat Funcional de Patología Vascular Cerebral, Hospital Clínic, Barcelona, Spain
| | - Anna M Planas
- Department of Neuroscience and Experimental Therapeutics, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036, Barcelona, Spain.
- Cerebrovascular Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
- University of Barcelona, Barcelona, Spain.
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19
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Paolini R, Molfetta R. CD155 and Its Receptors as Targets for Cancer Therapy. Int J Mol Sci 2023; 24:12958. [PMID: 37629138 PMCID: PMC10455395 DOI: 10.3390/ijms241612958] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/11/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
CD155, also known as the poliovirus receptor, is an adhesion molecule often overexpressed in tumors of different origins where it promotes cell migration and proliferation. In addition to this pro-tumorigenic function, CD155 plays an immunomodulatory role during tumor progression since it is a ligand for both the activating receptor DNAM-1 and the inhibitory receptor TIGIT, expressed on cytotoxic innate and adaptative lymphocytes. DNAM-1 is a well-recognized receptor involved in anti-tumor immune surveillance. However, in advanced tumor stages, TIGIT is up-regulated and acts as an immune checkpoint receptor, counterbalancing DNAM-1-mediated cancer cell clearance. Pre-clinical studies have proposed the direct targeting of CD155 on tumor cells as well as the enhancement of DNAM-1-mediated anti-tumor functions as promising therapeutic approaches. Moreover, immunotherapeutic use of anti-TIGIT blocking antibody alone or in combined therapy has already been included in clinical trials. The aim of this review is to summarize all these potential therapies, highlighting the still controversial role of CD155 during tumor progression.
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Affiliation(s)
| | - Rosa Molfetta
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy;
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Hermans D, Rodriguez-Mogeda C, Kemps H, Bronckaers A, de Vries HE, Broux B. Nectins and Nectin-like molecules drive vascular development and barrier function. Angiogenesis 2023; 26:349-362. [PMID: 36867287 DOI: 10.1007/s10456-023-09871-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/10/2023] [Indexed: 03/04/2023]
Abstract
Angiogenesis, barriergenesis, and immune cell migration are all key physiological events that are dependent on the functional characteristics of the vascular endothelium. The protein family of Nectins and Nectin-like molecules (Necls) is a group of cell adhesion molecules that are widely expressed by different endothelial cell types. The family includes four Nectins (Nectin-1 to -4) and five Necls (Necl-1 to -5) that either interact with each other by forming homo- and heterotypical interactions or bind to ligands expressed within the immune system. Nectin and Necl proteins are mainly described to play a role in cancer immunology and in the development of the nervous system. However, Nectins and Necls are underestimated players in the formation of blood vessels, their barrier properties, and in guiding transendothelial migration of leukocytes. This review summarizes their role in supporting the endothelial barrier through their function in angiogenesis, cell-cell junction formation, and immune cell migration. In addition, this review provides a detailed overview of the expression patterns of Nectins and Necls in the vascular endothelium.
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Affiliation(s)
- Doryssa Hermans
- Department of Immunology and Infection, UHasselt, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium
| | - Carla Rodriguez-Mogeda
- Molecular Cell Biology and Immunology, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands
| | - Hannelore Kemps
- Department of Cardio & Organ Systems, UHasselt, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium
- KU Leuven, Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, Leuven, Belgium
| | - Annelies Bronckaers
- Department of Cardio & Organ Systems, UHasselt, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium
| | - Helga E de Vries
- Molecular Cell Biology and Immunology, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands
| | - Bieke Broux
- Department of Immunology and Infection, UHasselt, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium.
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Imširović V, Lenartić M, Wensveen FM, Polić B, Jelenčić V. Largely preserved functionality after the combined loss of NKG2D, NCR1 and CD16 demonstrates the remarkable plasticity of NK cell responsiveness. Front Immunol 2023; 14:1191884. [PMID: 37520575 PMCID: PMC10374020 DOI: 10.3389/fimmu.2023.1191884] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/27/2023] [Indexed: 08/01/2023] Open
Abstract
Natural killer (NK) cells play an important role in the early defense against tumors and virally infected cells. Their function is thought to be controlled by the balance between activating and inhibitory receptors, which often compete for the same ligands. Several activating receptors expressed on virtually all NK cells lack an inhibitory partner, most notably CD16, NCR1 and NKG2D. We therefore hypothesized that a signal through at least one of these receptors is always required for full NK cell activation. We generated animals lacking all three receptors (TKO) and analyzed their NK cells. In vitro, TKO NK cells did not show reduced ability to kill tumor targets but displayed hyperresponsiveness to NK1.1 stimulation. In vivo, TKO animals had a minor reduction in their ability to control non-hematopoietic tumors and cytomegalovirus infection, which was the result of reduced NK cell activity. Together, our findings show that activating NK cell receptors without an inhibitory partner do not provide a 'master' signal but are integrated in the cumulative balance of activating and inhibitory signals. Their activity is controlled through regulation of the responsiveness and expression of other activating receptors. Our findings may be important for future development of NK cell-based cancer immunotherapy.
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22
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Hermans D, van Beers L, Broux B. Nectin Family Ligands Trigger Immune Effector Functions in Health and Autoimmunity. BIOLOGY 2023; 12:452. [PMID: 36979144 PMCID: PMC10045777 DOI: 10.3390/biology12030452] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/06/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
The superfamily of immunoglobulin cell-adhesion molecules (IgCAMs) is a well-known family of cell-adhesion molecules used for immune-cell extravasation and cell-cell interaction. Amongst others, this family includes DNAX accessory molecule 1 (DNAM-1/CD226), class-I-restricted T-cell-associated molecule (CRTAM/CD355), T-cell-activated increased late expression (Tactile/CD96), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), Nectins and Nectin-like molecules (Necls). Besides using these molecules to migrate towards inflammatory sites, their interactions within the immune system can support the immunological synapse with antigen-presenting cells or target cells for cytotoxicity, and trigger diverse effector functions. Although their role is generally described in oncoimmunity, this review emphasizes recent advances in the (dys)function of Nectin-family ligands in health, chronic inflammatory conditions and autoimmune diseases. In addition, this review provides a detailed overview on the expression pattern of Nectins and Necls and their ligands on different immune-cell types by focusing on human cell systems.
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Affiliation(s)
- Doryssa Hermans
- University MS Center, Campus Diepenbeek, 3590 Diepenbeek, Belgium; (D.H.); (L.v.B.)
- Department of Immunology and Infection, Biomedical Research Institute, University of Hasselt, 3590 Diepenbeek, Belgium
| | - Lisa van Beers
- University MS Center, Campus Diepenbeek, 3590 Diepenbeek, Belgium; (D.H.); (L.v.B.)
- Department of Immunology and Infection, Biomedical Research Institute, University of Hasselt, 3590 Diepenbeek, Belgium
| | - Bieke Broux
- University MS Center, Campus Diepenbeek, 3590 Diepenbeek, Belgium; (D.H.); (L.v.B.)
- Department of Immunology and Infection, Biomedical Research Institute, University of Hasselt, 3590 Diepenbeek, Belgium
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23
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CD96 as a Potential Immune Regulator in Cancers. Int J Mol Sci 2023; 24:ijms24021303. [PMID: 36674817 PMCID: PMC9866520 DOI: 10.3390/ijms24021303] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023] Open
Abstract
The discovery of CTLA-4 and PD-1 checkpoints has prompted scientific researchers and the pharmaceutical industry to develop and conduct extensive research on tumor-specific inhibitors. As a result, the list of potential immune checkpoint molecules is growing over time. Receptors for nectin and nectin-like proteins have recently emerged as promising targets for cancer immunotherapy. Potential immune checkpoints, including CD226, TIGIT, and CD96, belong to this receptor class. Among them, CD96 has received little attention. In this mini-review, we aim to discuss the basic biology of CD96 as well as the most recent relevant research on this as a promising candidate for cancer immunotherapy.
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Mannion AJ, Odell AF, Baker SM, Matthews LC, Jones PF, Cook GP. Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition. Front Cell Dev Biol 2023; 11:1129015. [PMID: 37138793 PMCID: PMC10150653 DOI: 10.3389/fcell.2023.1129015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/13/2023] [Indexed: 05/05/2023] Open
Abstract
CD146, also known as melanoma cell adhesion molecule (MCAM), is expressed in numerous cancers and has been implicated in the regulation of metastasis. We show that CD146 negatively regulates transendothelial migration (TEM) in breast cancer. This inhibitory activity is reflected by a reduction in MCAM gene expression and increased promoter methylation in tumour tissue compared to normal breast tissue. However, increased CD146/MCAM expression is associated with poor prognosis in breast cancer, a characteristic that is difficult to reconcile with inhibition of TEM by CD146 and its epigenetic silencing. Single cell transcriptome data revealed MCAM expression in multiple cell types, including the malignant cells, tumour vasculature and normal epithelium. MCAM expressing malignant cells were in the minority and expression was associated with epithelial to mesenchymal transition (EMT). Furthermore, gene expression signatures defining invasiveness and a stem cell-like phenotype were most strongly associated with mesenchymal-like tumour cells with low levels of MCAM mRNA, likely to represent a hybrid epithelial/mesenchymal (E/M) state. Our results show that high levels of MCAM gene expression are associated with poor prognosis in breast cancer because they reflect tumour vascularisation and high levels of EMT. We suggest that high levels of mesenchymal-like malignant cells reflect large populations of hybrid E/M cells and that low CD146 expression on these hybrid cells is permissive for TEM, aiding metastasis.
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Affiliation(s)
- Aarren J. Mannion
- Leeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United Kingdom
| | - Adam F. Odell
- Leeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United Kingdom
| | - Syed Murtuza Baker
- Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
| | - Laura C. Matthews
- Leeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United Kingdom
| | - Pamela F. Jones
- Leeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United Kingdom
| | - Graham P. Cook
- Leeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United Kingdom
- *Correspondence: Graham P. Cook,
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Liu WF, Quan B, Li M, Zhang F, Hu KS, Yin X. PVR-A Prognostic Biomarker Correlated with Immune Cell Infiltration in Hepatocellular Carcinoma. Diagnostics (Basel) 2022; 12:diagnostics12122953. [PMID: 36552960 PMCID: PMC9777148 DOI: 10.3390/diagnostics12122953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
The poliovirus receptor (PVR) is a member of the immunoglobulin superfamily (Ig SF) and is essential for the promotion of cancer cell proliferation and invasion. However, the correlation between PVR expression and prognosis as well as immune infiltration in hepatocellular carcinoma (HCC) remains unclear. The expression level of PVR was quantified using the Tumor and Tumor Immunity Evaluation Resource (TIMER) and Sangerbox. The Gene Expression Omnibus (GEO) database was used to validate the PVR expression. The receiver operating characteristic (ROC) curve was used to evaluate the feasibility of using PVR as a differentiating factor according to the area under curve (AUC) score. A PVR binding protein network was built using the STRING tool. An enrichment analysis using the R package clusterProfiler was used to explore the potential function of PVR. Immune infiltration analysis was calculated with ESTIMATE algorithms. We also assessed the correlation between PVR expression and immune infiltration by the single-sample Gene Set Enrichment Analysis (ssGSEA) method from the R package GSVA and TIMER database. The results showed that PVR was commonly overexpressed in multiple types of tumors including HCC. The data of GSE64041 confirmed the same result. The ROC curve suggested that PVR could be a potential diagnostic biomarker. Additionally, high mRNA expression of PVR in HCC was significantly correlated with poor overall survival (OS) and relapse free survival (RFS). Results also indicated correlations between PVR mRNA expression with the level of infiltration immune cells including B cells, CD8+ T cells, cytotoxic cells, DCs, CD56dim NK cells, pDCs, and Th2 cells. Furthermore, the PVR level was significantly correlated with immune markers for immunosuppressive cells in HCC. In conclusion, PVR might be an important regulator of tumor immune cell infiltration and a valuable prognostic biomarker in HCC. However, additional work is needed to fully elucidate the underlying mechanisms.
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Affiliation(s)
- Wen-Feng Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 136 Yi Xue Yuan Road, Shanghai 200032, China
| | - Bing Quan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 136 Yi Xue Yuan Road, Shanghai 200032, China
| | - Miao Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 136 Yi Xue Yuan Road, Shanghai 200032, China
| | - Feng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 136 Yi Xue Yuan Road, Shanghai 200032, China
| | - Ke-Shu Hu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 136 Yi Xue Yuan Road, Shanghai 200032, China
| | - Xin Yin
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 136 Yi Xue Yuan Road, Shanghai 200032, China
- Correspondence:
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Rogel A, Ibrahim FM, Thirdborough SM, Renart-Depontieu F, Birts CN, Buchan SL, Preville X, King EV, Al-Shamkhani A. Fcγ receptor-mediated cross-linking codefines the immunostimulatory activity of anti-human CD96 antibodies. JCI Insight 2022; 7:e158444. [PMID: 35998045 PMCID: PMC9675451 DOI: 10.1172/jci.insight.158444] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 08/19/2022] [Indexed: 11/17/2022] Open
Abstract
New strategies that augment T cell responses are required to broaden the therapeutic arsenal against cancer. CD96, TIGIT, and CD226 are receptors that bind to a communal ligand, CD155, and transduce either inhibitory or activating signals. The function of TIGIT and CD226 is established, whereas the role of CD96 remains ambiguous. Using a panel of engineered antibodies, we discovered that the T cell stimulatory activity of anti-CD96 antibodies requires antibody cross-linking and is potentiated by Fcγ receptors. Thus, soluble "Fc silent" anti-CD96 antibodies failed to stimulate human T cells, whereas the same antibodies were stimulatory after coating onto plastic surfaces. Remarkably, the activity of soluble anti-CD96 antibodies was reinstated by engineering the Fc domain to a human IgG1 isotype, and it was dependent on antibody trans-cross-linking by FcγRI. In contrast, neither human IgG2 nor variants with increased Fcγ receptor IIB binding possessed stimulatory activity. Anti-CD96 antibodies acted directly on T cells and augmented gene expression networks associated with T cell activation, leading to proliferation, cytokine secretion, and resistance to Treg suppression. Furthermore, CD96 expression correlated with survival in HPV+ head and neck squamous cell carcinoma, and its cross-linking activated tumor-infiltrating T cells, thus highlighting the potential of anti-CD96 antibodies in cancer immunotherapy.
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Affiliation(s)
- Anne Rogel
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Fathima M. Ibrahim
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Stephen M. Thirdborough
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | | | - Charles N. Birts
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Sarah L. Buchan
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | | | - Emma V. King
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Aymen Al-Shamkhani
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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27
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Xin H, Liu Y, Chen P, Yin T, Wang M, Liu T, Wen Z, Cheng Y. CD155 promotes radioresistance and malignancy of esophageal cancer by regulating Hippo-YAP pathway. Discov Oncol 2022; 13:53. [PMID: 35768666 PMCID: PMC9243211 DOI: 10.1007/s12672-022-00515-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/10/2022] [Indexed: 12/24/2022] Open
Abstract
The expression of CD155 has been observed to increase in various human cancers, but its role in the development of esophageal cancer (EC) is unclear. Radiotherapy is one of the primary therapeutic options for EC. However, radioresistance is still a severe issue in EC treatment. In this study, Oncomine database mining, immunohistochemistry, and survival analysis showed that higher expression of CD155 in patients with EC than in healthy controls. In vitro and in vivo, we found for the first time that irradiation increased the expression of CD155 in EC cells. CD155 knockdown inhibited cell proliferation and migration and tumor formation, and significantly increased radiosensitivity in EC. The in vivo model with high CD155 expression significantly promoted the proliferation and migration of EC cells. Furthermore, increased CD155 expression was associated with poor prognosis in patients with EC. CD155 regulated the Hippo-Yap pathway, influencing cell proliferation and migration. Therefore, CD155 is essential for the proliferation, migration, and radioresistance of EC. CD155 inhibition may be a viable strategy for improving radiation treatment efficacy in individuals with EC.
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Affiliation(s)
- Huixian Xin
- Department of Radiation Oncology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 250012, Jinan, Shandong, China
| | - Yuchen Liu
- Department of Radiation Oncology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 250012, Jinan, Shandong, China
| | - Pengxiang Chen
- Department of Radiation Oncology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 250012, Jinan, Shandong, China
| | - Tianwen Yin
- Department of Radiation Oncology, Shandong Cancer Hospital, and Institute, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Meijie Wang
- Department of Radiation Oncology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 250012, Jinan, Shandong, China
| | - Tianyu Liu
- Department of Radiation Oncology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 250012, Jinan, Shandong, China
| | - Zhihua Wen
- Department of Radiation Oncology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 250012, Jinan, Shandong, China.
| | - Yufeng Cheng
- Department of Radiation Oncology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 250012, Jinan, Shandong, China.
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28
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Li J, Zhao F, Qin Q, Yang L, Jiang Y, Hou Y, Wang Y, Zhou W, Fang L, Chen L. The Effect of CD226 on the Balance between Inflammatory Monocytes and Small Peritoneal Macrophages in Mouse Ulcerative Colitis. Immunol Invest 2022; 51:1833-1842. [PMID: 35468025 DOI: 10.1080/08820139.2022.2065921] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Ulcerative colitis (UC) is a refractory and recurring inflammatory bowel disease (IBD). Monocytes and macrophages are major components of the mononuclear phagocyte system (MPS), and the balance between inflammatory monocytes and small peritoneal macrophages plays important roles in UC. However, the mechanisms governing the balance between inflammatory monocytes and small peritoneal macrophages in UC need to be clarified further. Here, we found that the expression levels of CD226 on different subsets of monocytes/macrophages are varied in UC mice. The expression levels of CD226 on patrolling monocytes (pMos) and small peritoneal macrophages (SPMs) were markedly increased, while the expression levels of CD226 on inflammatory monocytes (iMos) were decreased in UC mice. Significantly, the percentage of iMos was enhanced while the percentage of SPMs were decreased in CD226 knockout UC mice compared with that in wildtype UC mice. Moreover, CD226 deficiency suppressed the migration capacity of macrophages. Therefore, our data suggest that CD226 plays critical roles in regulating the function and balance of monocytes/macrophages in mouse UC and targeting CD226 in MPS may be developed as a potent therapy for UC.
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Affiliation(s)
- Juan Li
- The College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.,Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Feng Zhao
- Department of Pulmonary and Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qi Qin
- The College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.,Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Liu Yang
- The College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.,Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yuan Jiang
- Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China.,School of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Yongli Hou
- Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yazhen Wang
- Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wenjing Zhou
- The College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.,Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Liang Fang
- Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lihua Chen
- The College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.,Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, China
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29
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Chiang EY, Mellman I. TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy. J Immunother Cancer 2022; 10:jitc-2022-004711. [PMID: 35379739 PMCID: PMC8981293 DOI: 10.1136/jitc-2022-004711] [Citation(s) in RCA: 113] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/08/2022] [Indexed: 12/22/2022] Open
Abstract
Recent advances in understanding the roles of immune checkpoints in allowing tumors to circumvent the immune system have led to successful therapeutic strategies that have fundamentally changed oncology practice. Thus far, immunotherapies against only two checkpoint targets have been approved, CTLA-4 and PD-L1/PD-1. Antibody blockade of these targets enhances the function of antitumor T cells at least in part by relieving inhibition of the T cell costimulatory receptor CD28. These successes have stimulated considerable interest in identifying other pathways that may bte targeted alone or together with existing immunotherapies. One such immune checkpoint axis is comprised of members of the PVR/nectin family that includes the inhibitory receptor T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT). Interestingly, TIGIT acts to regulate the activity of a second costimulatory receptor CD226 that works in parallel to CD28. There are currently over two dozen TIGIT-directed blocking antibodies in various phases of clinical development, testament to the promise of modulating this pathway to enhance antitumor immune responses. In this review, we discuss the role of TIGIT as a checkpoint inhibitor, its interplay with the activating counter-receptor CD226, and its status as the next advance in cancer immunotherapy.
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Affiliation(s)
- Eugene Y Chiang
- Cancer Immunology, Genentech Inc, South San Francisco, California, USA
| | - Ira Mellman
- Cancer Immunology, Genentech Inc, South San Francisco, California, USA
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30
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Kuske M, Haist M, Jung T, Grabbe S, Bros M. Immunomodulatory Properties of Immune Checkpoint Inhibitors-More than Boosting T-Cell Responses? Cancers (Basel) 2022; 14:1710. [PMID: 35406483 PMCID: PMC8996886 DOI: 10.3390/cancers14071710] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 12/11/2022] Open
Abstract
The approval of immune checkpoint inhibitors (ICI) that serve to enhance effector T-cell anti-tumor responses has strongly improved success rates in the treatment of metastatic melanoma and other tumor types. The currently approved ICI constitute monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein (CTLA)-4 and anti-programmed cell death (PD)-1. By this, the T-cell-inhibitory CTLA-4/CD80/86 and PD-1/PD-1L/2L signaling axes are inhibited. This leads to sustained effector T-cell activity and circumvents the immune evasion of tumor cells, which frequently upregulate PD-L1 expression and modulate immune checkpoint molecule expression on leukocytes. As a result, profound clinical responses are observed in 40-60% of metastatic melanoma patients. Despite the pivotal role of T effector cells for triggering anti-tumor immunity, mounting evidence indicates that ICI efficacy may also be attributable to other cell types than T effector cells. In particular, emerging research has shown that ICI also impacts innate immune cells, such as myeloid cells, natural killer cells and innate lymphoid cells, which may amplify tumoricidal functions beyond triggering T effector cells, and thus improves clinical efficacy. Effects of ICI on non-T cells may additionally explain, in part, the character and extent of adverse effects associated with treatment. Deeper knowledge of these effects is required to further develop ICI treatment in terms of responsiveness of patients to treatment, to overcome resistance to ICI and to alleviate adverse effects. In this review we give an overview into the currently known immunomodulatory effects of ICI treatment in immune cell types other than the T cell compartment.
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Affiliation(s)
| | | | | | | | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.K.); (M.H.); (T.J.); (S.G.)
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31
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Kuksa PP, Liu CL, Fu W, Qu L, Zhao Y, Katanic Z, Clark K, Kuzma AB, Ho PC, Tzeng KT, Valladares O, Chou SY, Naj AC, Schellenberg GD, Wang LS, Leung YY. Alzheimer's Disease Variant Portal: A Catalog of Genetic Findings for Alzheimer's Disease. J Alzheimers Dis 2022; 86:461-477. [PMID: 35068457 PMCID: PMC9028687 DOI: 10.3233/jad-215055] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Recent Alzheimer's disease (AD) genetics findings from genome-wide association studies (GWAS) span progressively larger and more diverse populations and outcomes. Currently, there is no up-to-date resource providing harmonized and searchable information on all AD genetic associations found by GWAS, nor linking the reported genetic variants and genes with functional and genomic annotations. OBJECTIVE Create an integrated/harmonized, and literature-derived collection of population-specific AD genetic associations. METHODS We developed the Alzheimer's Disease Variant Portal (ADVP), an extensive collection of associations curated from >200 GWAS publications from Alzheimer's Disease Genetics Consortium and other consortia. Genetic associations were systematically extracted, harmonized, and annotated from both the genome-wide significant and suggestive loci reported in these publications. To ensure consistent representation of AD genetic findings, all the extracted genetic association information was harmonized across specifically designed publication, variant, and association categories. RESULTS ADVP V1.0 (February 2021) catalogs 6,990 associations related to disease-risk, expression quantitative traits, endophenotypes, or neuropathology. This extensive harmonization effort led to a catalog containing >900 loci, >1,800 variants, >80 cohorts, and 8 populations. Besides, ADVP provides investigators with a seamless integration of genomic and publicly available functional annotations across multiple databases per harmonized variant and gene records, thus facilitating further understanding and analyses of these genetics findings. CONCLUSION ADVP is a valuable resource for investigators to quickly and systematically explore high-confidence AD genetic findings and provides insights into population-specific AD genetic architecture. ADVP is continually maintained and enhanced by NIAGADS and is freely accessible at https://advp.niagads.org.
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Affiliation(s)
- Pavel P. Kuksa
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Chia-Lun Liu
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Wei Fu
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Liming Qu
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Yi Zhao
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Zivadin Katanic
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Kaylyn Clark
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Amanda B. Kuzma
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Pei-Chuan Ho
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Kai-Teh Tzeng
- Department of Economics, Lehigh University, Bethlehem, PA, USA
| | - Otto Valladares
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Shin-Yi Chou
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Economics, Lehigh University, Bethlehem, PA, USA
| | - Adam C. Naj
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Gerard D. Schellenberg
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Li-San Wang
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Yuk Yee Leung
- Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
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Ma J, Hu W, Zhang D, Xie J, Duan C, Liu Y, Wang Y, Xu X, Cheng K, Jin B, Zhang Y, Zhuang R. CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype. J Transl Med 2021; 19:477. [PMID: 34823548 PMCID: PMC8620575 DOI: 10.1186/s12967-021-03150-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/17/2021] [Indexed: 12/30/2022] Open
Abstract
Obesity is associated with chronic low-grade inflammation, contributing to an increasing prevalence of chronic metabolic diseases, such as insulin resistance, non-alcoholic fatty liver disease (NALFD), and steatohepatitis. Macrophages are the predominant immune cells in adipose tissues. Adipose tissue macrophages (ATMs) would switch to pro-inflammatory M1 state during obesity, causing local and systemic inflammation. However, the regulatory mechanism of ATMs has not yet been well described within this process. Using a high-fat diet (HFD)–induced mouse obesity model, we found that the costimulatory molecule CD226 was highly expressed on ATMs and knockout (KO) of CD226 alleviated obesity caused by HFD. Loss of CD226 reduced the accumulation of ATMs and hindered macrophage M1 polarization, with lower serum proinflammatory cytokine levels. Furthermore, deficiency of CD226 on ATMs decreased the phosphorylation levels of VAV1, AKT, and FOXO1 and thereby upregulated PPAR-γ. Further administration of PPAR-γ inhibitor restored M1 phenotype in CD226KO ATMs. In summary, loss of CD226 alleviates the HFD-induced obesity and systemic inflammation through inhibition of the accumulation and M1 polarization of ATMs in which PPAR-γ-dependent signaling pathway is involved, suggesting that CD226 may be identified as a potential molecular target for the clinical treatment of obesity.
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Affiliation(s)
- Jingchang Ma
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Wei Hu
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Dongliang Zhang
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Jiangang Xie
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Chujun Duan
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Yitian Liu
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Yuling Wang
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Xuexue Xu
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, 710072, Shaanxi, China
| | - Kun Cheng
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Boquan Jin
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Yuan Zhang
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, 710072, Shaanxi, China.
| | - Ran Zhuang
- Department of Immunology, Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, Shaanxi, China. .,Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, 710072, Shaanxi, China.
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Holder KA, Burt K, Grant MD. TIGIT blockade enhances NK cell activity against autologous HIV-1-infected CD4 + T cells. Clin Transl Immunology 2021; 10:e1348. [PMID: 34707863 PMCID: PMC8527024 DOI: 10.1002/cti2.1348] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 09/21/2021] [Accepted: 09/27/2021] [Indexed: 12/17/2022] Open
Abstract
Objectives During chronic human immunodeficiency virus (HIV)‐1 infection, inhibitory molecules upregulated on lymphocytes contribute to effector cell dysfunction and immune exhaustion. People living with HIV (PLWH) are at greater risk for age‐related morbidities, an issue magnified by human cytomegalovirus (CMV) coinfection. As CMV infection modifies natural killer (NK) cell properties and NK cells contribute to protection against HIV‐1 infection, we considered the role of T‐cell immunoreceptor with immunoglobulin and intracellular tyrosine inhibitory motif domains (TIGIT) in NK cell‐based HIV‐1 immunotherapy and elimination strategies. Methods We measured TIGIT expression on immune cell subsets of 95 PLWH and assessed its impact on NK cell function, including elimination of autologous CD4+ T cells infected through reactivation of endogenous HIV‐1. Results TIGIT was expressed on CD4+ T cells, CD8+ T cells and NK cells from PLWH. Although TIGIT levels on T cells correlated with HIV‐1 disease progression, the extent of TIGIT expression on NK cells more closely paralleled adaptation to CMV. TIGIT interacts with its predominant ligand, poliovirus receptor (PVR), to inhibit effector cell functions. Circulating CD4+ T cells from PLWH more frequently expressed PVR than HIV‐seronegative controls, and PVR expression was enriched in CD4+ T cells replicating HIV‐1 ex vivo. Treatment with anti‐TIGIT monoclonal antibodies increased NK cell HIV‐1‐specific antibody‐dependent cytotoxicity in vitro and ex vivo. Conclusion Blocking TIGIT may be an effective strategy to invigorate antibody‐dependent NK cell activity against HIV‐1 activated in cellular reservoirs for cure or treatment strategies.
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Affiliation(s)
- Kayla A Holder
- Immunology and Infectious Diseases Program Division of BioMedical Sciences Faculty of Medicine Memorial University of Newfoundland St. John's NL Canada
| | | | - Michael D Grant
- Immunology and Infectious Diseases Program Division of BioMedical Sciences Faculty of Medicine Memorial University of Newfoundland St. John's NL Canada
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Sant'Ana AN, Araújo AB, Gonçalves FDC, Paz AH. Effects of living and metabolically inactive mesenchymal stromal cells and their derivatives on monocytes and macrophages. World J Stem Cells 2021; 13:1160-1176. [PMID: 34630856 PMCID: PMC8474715 DOI: 10.4252/wjsc.v13.i9.1160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/01/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent and self-renewing stem cells that have great potential as cell therapy for autoimmune and inflammatory disorders, as well as for other clinical conditions, due to their immunoregulatory and regenerative properties. MSCs modulate the inflammatory milieu by releasing soluble factors and acting through cell-to-cell mechanisms. MSCs switch the classical inflammatory status of monocytes and macrophages towards a non-classical and anti-inflammatory phenotype. This is characterized by an increased secretion of anti-inflammatory cytokines, a decreased release of pro-inflammatory cytokines, and changes in the expression of cell membrane molecules and in metabolic pathways. The MSC modulation of monocyte and macrophage phenotypes seems to be critical for therapy effectiveness in several disease models, since when these cells are depleted, no immunoregulatory effects are observed. Here, we review the effects of living MSCs (metabolically active cells) and metabolically inactive MSCs (dead cells that lost metabolic activity by induced inactivation) and their derivatives (extracellular vesicles, soluble factors, extracts, and microparticles) on the profile of macrophages and monocytes and the implications for immunoregulatory and reparative processes. This review includes mechanisms of action exhibited in these different therapeutic approaches, which induce the anti-inflammatory properties of monocytes and macrophages. Finally, we overview several possibilities of therapeutic applications of these cells and their derivatives, with results regarding monocytes and macrophages in animal model studies and some clinical trials.
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Affiliation(s)
- Alexia Nedel Sant'Ana
- Laboratório de Células Tecidos e Genes, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
| | - Anelise Bergmann Araújo
- Centro de Processamento Celular, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil.
| | | | - Ana Helena Paz
- Laboratório de Células Tecidos e Genes, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
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Nandi SS, Gohil T, Sawant SA, Lambe UP, Ghosh S, Jana S. CD155: A Key Receptor Playing Diversified Roles. Curr Mol Med 2021; 22:594-607. [PMID: 34514998 DOI: 10.2174/1566524021666210910112906] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 06/16/2021] [Accepted: 06/20/2021] [Indexed: 11/22/2022]
Abstract
Cluster of differentiation (CD155), formerly identified as poliovirus receptor (PVR) and later as immunoglobulin molecule involved in cell adhesion, proliferation, invasion and migration. It is a surface protein expressed mostly on normal and transformed malignant cells. The expression of the receptor varies based on the origin of tissue. The expression of the protein is determined by factors involved in sonic hedgehog pathway, Ras-MEK-ERK pathway and during stress conditions like DNA damage response. The protein uses alternate splicing mechanism, producing four isoforms - two being soluble (CD155β and CD155γ) and two being transmembrane protein (CD155α and CD155δ). Apart from being a viral receptor, researchers have identified CD155 having important roles in cancer research and cell signaling field. The receptor is recognized as biomarker for identifying cancerous tissue. The receptor interacts with molecules involved in cells defense mechanism. The immune-surveillance role of CD155 is being deciphered to understand the mechanistic approach it utilizes as onco-immunologic molecule. CD155 is a non-MHC-I ligand which helps in identifying non-self to NK cells via an inhibitory TIGIT ligand. The TIGIT-CD155 pathway is a novel MHC-I-independent education mechanism for cell tolerance and activation of NK cell. The receptor also has a role in metastasis of cancer and trans endothelial mechanism. In this review, authors discuss the virus-host interaction that occurs via single transmembrane receptor, the poliovirus infection pathway, which is being exploited as therapeutic pathway. The oncolytic virotherapy is now promising way for curing cancer.
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Affiliation(s)
- Shyam Sundar Nandi
- National Institute of Virology, (Mumbai unit), (Formerly Enterovirus Research Centre). Haffkine Institute Compound, Indian Council of Medical Research, A. D. Marg, Parel. Mumbai-12. India
| | - Trupti Gohil
- National Institute of Virology, (Mumbai unit), (Formerly Enterovirus Research Centre). Haffkine Institute Compound, Indian Council of Medical Research, A. D. Marg, Parel. Mumbai-12. India
| | - Sonali Ankush Sawant
- National Institute of Virology, (Mumbai unit), (Formerly Enterovirus Research Centre). Haffkine Institute Compound, Indian Council of Medical Research, A. D. Marg, Parel. Mumbai-12. India
| | - Upendra Pradeep Lambe
- National Institute of Virology, (Mumbai unit), (Formerly Enterovirus Research Centre). Haffkine Institute Compound, Indian Council of Medical Research, A. D. Marg, Parel. Mumbai-12. India
| | - Sudip Ghosh
- Molecular Biology Division, ICMR-National Institute of Nutrition, Jamai-Osmania PO, Hyderabad. India
| | - Snehasis Jana
- Trivedi Science Research Laboratory Pvt Ltd., Thane-West, Maharashtra-400604. India
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Chashchina A, Märklin M, Hinterleitner C, Salih HR, Heitmann JS, Klimovich B. DNAM-1/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis. Sci Rep 2021; 11:18012. [PMID: 34504191 PMCID: PMC8429762 DOI: 10.1038/s41598-021-97400-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/20/2021] [Indexed: 11/09/2022] Open
Abstract
DNAM-1 is reportedly expressed on cytotoxic T and NK cells and, upon interaction with its ligands CD112 and CD155, plays an important role in tumor immunosurveillance. It has also been reported to be functionally expressed by myeloid cells, but expression and function on malignant cells of the myeloid lineage have not been studied so far. Here we analyzed expression of DNAM-1 in leukemic cells of acute myeloid leukemia (AML) patients. We found substantial levels of DNAM-1 to be expressed on leukemic blasts in 48 of 62 (> 75%) patients. Interaction of DNAM-1 with its ligands CD112 and CD155 induced release of the immunomodulatory cytokines IL-6, IL-8 IL-10 and TNF-α by AML cells and DNAM-1 expression correlated with a more differentiated phenotype. Multivariate analysis did not show any association of DNAM-1 positivity with established risk factors, but expression was significantly associated with clinical disease course: patients with high DNAM-1 surface levels had significantly longer progression-free and overall survival compared to DNAM-1low patients, independently whether patients had undergone allogenic stem cell transplantation or not. Together, our findings unravel a functional role of DNAM-1 in AML pathophysiology and identify DNAM-1 as a potential novel prognostic maker in AML.
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Affiliation(s)
- Anna Chashchina
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany
| | - Melanie Märklin
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany
| | - Clemens Hinterleitner
- DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany.,Department of Medical Oncology and Pulmonology, University Hospital Tübingen, 72076, Tübingen, Germany
| | - Helmut R Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany
| | - Jonas S Heitmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany. .,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany.
| | - Boris Klimovich
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany
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Marderstein AR, Kulm S, Peng C, Tamimi R, Clark AG, Elemento O. A polygenic-score-based approach for identification of gene-drug interactions stratifying breast cancer risk. Am J Hum Genet 2021; 108:1752-1764. [PMID: 34363748 PMCID: PMC8456164 DOI: 10.1016/j.ajhg.2021.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/16/2021] [Indexed: 12/24/2022] Open
Abstract
An individual's genetics can dramatically influence breast cancer (BC) risk. Although clinical measures for prevention do exist, non-invasive personalized measures for reducing BC risk are limited. Commonly used medications are a promising set of modifiable factors, but no previous study has explored whether a range of widely taken approved drugs modulate BC genetics. In this study, we describe a quantitative framework for exploring the interaction between the genetic susceptibility of BC and medication usage among UK Biobank women. We computed BC polygenic scores (PGSs) that summarize BC genetic risk and find that the PGS explains nearly three-times greater variation in disease risk within corticosteroid users compared to non-users. We map 35 genes significantly interacting with corticosteroid use (FDR < 0.1), highlighting the transcription factor NRF2 as a common regulator of gene-corticosteroid interactions in BC. Finally, we discover a regulatory variant strongly stratifying BC risk according to corticosteroid use. Within risk allele carriers, 18.2% of women taking corticosteroids developed BC, compared to 5.1% of the non-users (with an HR = 3.41 per-allele within corticosteroid users). In comparison, there are no differences in BC risk within the reference allele homozygotes. Overall, this work highlights the clinical relevance of gene-drug interactions in disease risk and provides a roadmap for repurposing biobanks in drug repositioning and precision medicine.
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Affiliation(s)
- Andrew R Marderstein
- Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Institute of Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Department of Computational Biology, Cornell University, Ithaca, NY 14850, USA
| | - Scott Kulm
- Institute of Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Cheng Peng
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Rulla Tamimi
- Population Health Sciences, Weill Cornell Medicine, New York, NY 10065, USA
| | - Andrew G Clark
- Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Department of Computational Biology, Cornell University, Ithaca, NY 14850, USA.
| | - Olivier Elemento
- Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Institute of Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
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TIGIT Can Exert Immunosuppressive Effects on CD8+ T Cells by the CD155/TIGIT Signaling Pathway for Hepatocellular Carcinoma In Vitro. J Immunother 2021; 43:236-243. [PMID: 32804915 PMCID: PMC7566309 DOI: 10.1097/cji.0000000000000330] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Supplemental Digital Content is available in the text. The efficacy of adoptive cellular immunotherapy against cancer cells is limited due to the presence of immunosuppressive cells within the solid tumor microenvironment. The upregulation of certain coinhibitory receptors may lead to exhaustion of the immune effector cells. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune inhibitory receptor expressed by regulatory T cells and activated T cells and natural killer cells. The aim of this study was to determine the immunosuppressive effects of CD155/TIGIT signaling on CD8+ T cells of adoptive cellular immunotherapy in hepatocellular carcinoma (HCC). Our studies found that CD155 was overexpressed in HCC, and CD155hi HCC cells upregulated TIGIT on CD8+ T cells, which decreased the secretion of interferon-γ, tumor necrosis factor-α, and interleukin-17A and increased that of interleukin-10 from the effector cells. However, TIGIT blockade or CD155-knockdown reversed the inhibitory effect of HCC cells on CD8+ T-cell effector function. These results indicate that TIGIT can exert an immunosuppressive effect on CD8 T cells by modulating cytokine production through CD155, and is a promising target to optimize adoptive cellular immunotherapy against HCC.
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Rothlin CV, Ghosh S. Lifting the innate immune barriers to antitumor immunity. J Immunother Cancer 2021; 8:jitc-2020-000695. [PMID: 32273348 PMCID: PMC7254113 DOI: 10.1136/jitc-2020-000695] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2020] [Indexed: 12/17/2022] Open
Abstract
The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.
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Affiliation(s)
- Carla V Rothlin
- Immunobiology, Yale School of Medicine, New Haven, CT 06519, United States .,Pharmacology, Yale School of Medicine, New Haven, CT 06519, United States
| | - Sourav Ghosh
- Pharmacology, Yale School of Medicine, New Haven, CT 06519, United States .,Neurology, Yale School of Medicine, New Haven, CT 06519, United States
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BCL9 regulates CD226 and CD96 checkpoints in CD8 + T cells to improve PD-1 response in cancer. Signal Transduct Target Ther 2021; 6:313. [PMID: 34417435 PMCID: PMC8379253 DOI: 10.1038/s41392-021-00730-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 07/18/2021] [Accepted: 07/23/2021] [Indexed: 02/07/2023] Open
Abstract
To date, the overall response rate of PD-1 blockade remains unsatisfactory, partially due to limited understanding of tumor immune microenvironment (TIME). B-cell lymphoma 9 (BCL9), a key transcription co-activator of the Wnt pathway, is highly expressed in cancers. By genetic depletion and pharmacological inhibition of BCL9 in tumors, we found that BCL9 suppression reduced tumor growth, promoted CD8+ T cell tumor infiltration, and enhanced response to anti-PD-1 treatment in mouse colon cancer models. To determine the underlying mechanism of BCL9's role in TIME regulation, single-cell RNA-seq was applied to reveal cellular landscape and transcription differences in the tumor immune microenvironment upon BCL9 inhibition. CD155-CD226 and CD155-CD96 checkpoints play key roles in cancer cell/CD8+ T cell interaction. BCL9 suppression induces phosphorylation of VAV1 in CD8+ T cells and increases GLI1 and PATCH expression to promote CD155 expression in cancer cells. In The Cancer Genome Atlas database analysis, we found that BCL9 expression is positively associated with CD155 and negatively associated with CD226 expression. BCL9 is also linked to adenomatous polyposis coli (APC) mutation involved in patient survival following anti-PD-1 treatment. This study points to cellular diversity within the tumor immune microenvironment affected by BCL9 inhibition and provides new insights into the role of BCL9 in regulating CD226 and CD96 checkpoints.
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Bottino C, Dondero A, Castriconi R. Inhibitory axes impacting on the activity and fate of Innate Lymphoid Cells. Mol Aspects Med 2021; 80:100985. [PMID: 34176653 DOI: 10.1016/j.mam.2021.100985] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/05/2021] [Accepted: 06/06/2021] [Indexed: 01/02/2023]
Abstract
In neoplastic patients, an effective immune response ideally should be achieved by the coordinated action of different immune cells with tumor-suppressive functions. These include the more cytolytic members of the Innate Lymphoid Cells (ILCs) family represented by the Natural Killer (NK) cells, whose activities in cancer patients, however, can be hampered by several inhibitory signals. These are generated by membrane-bound and soluble molecules that, interacting with specific inhibitory receptors, create inhibitory axes impacting the NK cell differentiation and effector functions. These breaks, which now represent major immunotherapeutic targets, may be sensitive to interferon (IFN)-γ, whose source, in vivo, is represented by different cell types including the NK and ILC1. Since also ILCs can express receptors of the inhibitory axes like PD-1 and TIGIT, their therapeutic blockade might further amplify the IFN-γ release that, as an unwanted side effect, would promote the onset of NK cell-resistant tumor variants (NKRTV) expressing ligands involved in inhibitory axes. These variants might also arise from the activity of other cytokines such as IL-27, which can increase the expression of HLA class I and PD-Ls in different cell types, including tumor cells. Besides the amplification of membrane-bound inhibitory axes, tumors can reduce the number of infiltrating cytolytic ILCs, promote the recruitment of poorly cytolytic NK cell subsets, and manipulate to their advantage the infiltrating immune cells, which acquire tumor-promoting activities. This occurs thanks to the production of soluble factors including TGF-β1 and IL-18 that, alone or in combination, modify the activating and chemokine receptor repertoire of NK cells, and induce the ILCs differentiation towards cells ineffective in fighting cancer or, even worse, with tumor-promoting functions. The present review aims to present and discuss major inhibitory axes impacting on ILCs functions, migration, and differentiation with a major focus on tumor context.
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Affiliation(s)
- Cristina Bottino
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy; IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Alessandra Dondero
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
| | - Roberta Castriconi
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy.
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Liu L, Wang Y, Geng C, Wang A, Han S, You X, Sun Y, Zhang J, Lu W, Zhang Y. CD155 Promotes the Progression of Cervical Cancer Cells Through AKT/mTOR and NF-κB Pathways. Front Oncol 2021; 11:655302. [PMID: 34164340 PMCID: PMC8216081 DOI: 10.3389/fonc.2021.655302] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/19/2021] [Indexed: 11/24/2022] Open
Abstract
Expression of the immunoglobulin superfamily member CD155 was increased in a variety of human malignancies, but the role of CD155 in tumorigenesis and tumor development in cervical cancer has not been elucidated. In this study, immunohistochemistry and enzyme-linked immunosorbent assay analyses showed that CD155 expression gradually increases with the degree of cervical lesions. In vitro and in vivo, reducing the expression of CD155 inhibited cell proliferation, cell viability and tumor formation and arrested the cell cycle in G0/G1 phase. Antibody array-based profiling of protein phosphorylation revealed that CD155 knockdown can inhibited the AKT/mTOR/NF-κB pathway and activated autophagy and apoptosis; the opposite effects were observed upon CD155 has overexpression. We proved that there is an interaction between CD155 and AKT by immunoprecipitation. We further confirmed the mechanism between CD155 and AKT/mTOR/NF-κB through rescue experiments. AKT knockdown reversed the anti-apoptotic effects and activation of the AKT/mTOR/NF-κB pathway induced by CD155 overexpression. Our research demonstrated that CD155 can interact with AKT to form a complex, activates the AKT/mTOR/NF-κB pathway and inhibit autophagy and apoptosis. Thus, CD155 is a potential screening and therapeutic biomarker for cervical cancer.
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Affiliation(s)
- Lu Liu
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Ying Wang
- Department of Obstetrics and Gynecology, Yidu Central Hospital of Weifang, Weifang, China
| | - Chen Geng
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Aihong Wang
- Department of Obstetrics and Gynaecology, Feicheng Hospital Affiliated to Shandong First Medical University, Tai'an, China
| | - Sai Han
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Xuewu You
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Yu Sun
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Junhua Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Wei Lu
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Youzhong Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Gynecologic Oncology of Shandong Province, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
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HCMV-controlling NKG2C+ NK cells originate from novel circulating inflammatory precursors. J Allergy Clin Immunol 2021; 147:2343-2357. [DOI: 10.1016/j.jaci.2020.12.648] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 11/26/2020] [Accepted: 12/04/2020] [Indexed: 12/18/2022]
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Viral Interactions with Adaptor-Protein Complexes: A Ubiquitous Trait among Viral Species. Int J Mol Sci 2021; 22:ijms22105274. [PMID: 34067854 PMCID: PMC8156722 DOI: 10.3390/ijms22105274] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 12/22/2022] Open
Abstract
Numerous viruses hijack cellular protein trafficking pathways to mediate cell entry or to rearrange membrane structures thereby promoting viral replication and antagonizing the immune response. Adaptor protein complexes (AP), which mediate protein sorting in endocytic and secretory transport pathways, are one of the conserved viral targets with many viruses possessing AP-interacting motifs. We present here different mechanisms of viral interference with AP complexes and the functional consequences that allow for efficient viral propagation and evasion of host immune defense. The ubiquity of this phenomenon is evidenced by the fact that there are representatives for AP interference in all major viral families, covered in this review. The best described examples are interactions of human immunodeficiency virus and human herpesviruses with AP complexes. Several other viruses, like Ebola, Nipah, and SARS-CoV-2, are pointed out as high priority disease-causative agents supporting the need for deeper understanding of virus-AP interplay which can be exploited in the design of novel antiviral therapies.
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45
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Arif N, Zinnhardt M, Nyamay’Antu A, Teber D, Brückner R, Schaefer K, Li Y, Trappmann B, Grashoff C, Vestweber D. PECAM-1 supports leukocyte diapedesis by tension-dependent dephosphorylation of VE-cadherin. EMBO J 2021; 40:e106113. [PMID: 33604918 PMCID: PMC8090850 DOI: 10.15252/embj.2020106113] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 01/15/2021] [Accepted: 01/27/2021] [Indexed: 01/21/2023] Open
Abstract
Leukocyte extravasation is an essential step during the immune response and requires the destabilization of endothelial junctions. We have shown previously that this process depends in vivo on the dephosphorylation of VE-cadherin-Y731. Here, we reveal the underlying mechanism. Leukocyte-induced stimulation of PECAM-1 triggers dissociation of the phosphatase SHP2 which then directly targets VE-cadherin-Y731. The binding site of PECAM-1 for SHP2 is needed for VE-cadherin dephosphorylation and subsequent endocytosis. Importantly, the contribution of PECAM-1 to leukocyte diapedesis in vitro and in vivo was strictly dependent on the presence of Y731 of VE-cadherin. In addition to SHP2, dephosphorylation of Y731 required Ca2+ -signaling, non-muscle myosin II activation, and endothelial cell tension. Since we found that β-catenin/plakoglobin mask VE-cadherin-Y731 and leukocyte docking to endothelial cells exert force on the VE-cadherin-catenin complex, we propose that leukocytes destabilize junctions by PECAM-1-SHP2-triggered dephosphorylation of VE-cadherin-Y731 which becomes accessible by actomyosin-mediated mechanical force exerted on the VE-cadherin-catenin complex.
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Affiliation(s)
- Nida Arif
- Max Planck Institute for Molecular BiomedicineMünsterGermany
| | - Maren Zinnhardt
- Max Planck Institute for Molecular BiomedicineMünsterGermany
| | | | - Denise Teber
- Max Planck Institute for Molecular BiomedicineMünsterGermany
| | - Randy Brückner
- Max Planck Institute for Molecular BiomedicineMünsterGermany
| | | | - Yu‐Tung Li
- Max Planck Institute for Molecular BiomedicineMünsterGermany
| | | | - Carsten Grashoff
- Institute for Molecular Cell BiologyUniversity of MünsterMünsterGermany
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46
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Harwood JC, Leonenko G, Sims R, Escott-Price V, Williams J, Holmans P. Defining functional variants associated with Alzheimer's disease in the induced immune response. Brain Commun 2021; 3:fcab083. [PMID: 33959712 PMCID: PMC8087896 DOI: 10.1093/braincomms/fcab083] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 12/14/2022] Open
Abstract
Defining the mechanisms involved in the aetiology of Alzheimer's disease from genome-wide association studies alone is challenging since Alzheimer's disease is polygenic and most genetic variants are non-coding. Non-coding Alzheimer's disease risk variants can influence gene expression by affecting miRNA binding and those located within enhancers and within CTCF sites may influence gene expression through alterations in chromatin states. In addition, their function can be cell-type specific. They can function specifically in microglial enhancers thus affecting gene expression in the brain. Hence, transcriptome-wide association studies have been applied to test the genetic association between disease risk and cell-/tissue-specific gene expression. Many Alzheimer's disease-associated loci are involved in the pathways of the innate immune system. Both microglia, the primary immune cells of the brain, and monocytes which can infiltrate the brain and differentiate into activated macrophages, have roles in neuroinflammation and β-amyloid clearance through phagocytosis. In monocytes the function of regulatory variants can be context-specific after immune stimulation. To dissect the variants associated with Alzheimer's disease in the context of monocytes, we utilized data from naïve monocytes and following immune stimulation in vitro, in combination with genome-wide association studies of Alzheimer's disease in transcriptome-wide association studies. Of the nine genes with statistically independent transcriptome-wide association signals, seven are located in known Alzheimer's disease risk loci: BIN1, PTK2B, SPI1, MS4A4A, MS4A6E, APOE and PVR. The transcriptome-wide association signal for MS4A6E, PTK2B and PVR and the direction of effect replicated in an independent genome-wide association studies. Our analysis identified two novel candidate genes for Alzheimer's disease risk, LACTB2 and PLIN2/ADRP. LACTB2 replicated in a transcriptome-wide association study using independent expression weights. LACTB2 and PLIN2/ADRP are involved in mitochondrial function and lipid metabolism, respectively. Comparison of transcriptome-wide association study results from monocytes, whole blood and brain showed that the signal for PTK2B is specific to blood and MS4A6E is specific to LPS stimulated monocytes.
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Affiliation(s)
- Janet C Harwood
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Ganna Leonenko
- UK Dementia Research Institute at Cardiff University, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Rebecca Sims
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Valentina Escott-Price
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
- UK Dementia Research Institute at Cardiff University, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Julie Williams
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
- UK Dementia Research Institute at Cardiff University, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Peter Holmans
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
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47
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Grönloh MLB, Arts JJG, van Buul JD. Neutrophil transendothelial migration hotspots - mechanisms and implications. J Cell Sci 2021; 134:134/7/jcs255653. [PMID: 33795378 DOI: 10.1242/jcs.255653] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
During inflammation, leukocytes circulating in the blood stream exit the vasculature in a process called leukocyte transendothelial migration (TEM). The current paradigm of this process comprises several well-established steps, including rolling, adhesion, crawling, diapedesis and sub-endothelial crawling. Nowadays, the role of the endothelium in transmigration is increasingly appreciated. It has been established that leukocyte exit sites on the endothelium and in the pericyte layer are in fact not random but instead may be specifically recognized by migrating leukocytes. Here, we review the concept of transmigration hotspots, specific sites in the endothelial and pericyte layer where most transmigration events take place. Chemokine cues, adhesion molecules and membrane protrusions as well as physical factors, such as endothelial junction stability, substrate stiffness, the presence of pericytes and basement membrane composition, may all contribute to local hotspot formation to facilitate leukocytes exiting the vasculature. In this Review, we discuss the biological relevance of such hotspots and put forward multiple mechanisms and factors that determine a functional TEM hotspot.
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Affiliation(s)
- Max L B Grönloh
- Molecular Cell Biology Lab, Dept. Plasma proteins, Molecular and Cellular Homeostasis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066CX, The Netherlands.,Leeuwenhoek Centre for Advanced Microscopy (LCAM), Molecular Cytology section at Swammerdam Institute for Life Sciences (SILS) at University of Amsterdam, Amsterdam 1066CX, The Netherlands
| | - Janine J G Arts
- Molecular Cell Biology Lab, Dept. Plasma proteins, Molecular and Cellular Homeostasis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066CX, The Netherlands.,Leeuwenhoek Centre for Advanced Microscopy (LCAM), Molecular Cytology section at Swammerdam Institute for Life Sciences (SILS) at University of Amsterdam, Amsterdam 1066CX, The Netherlands
| | - Jaap D van Buul
- Molecular Cell Biology Lab, Dept. Plasma proteins, Molecular and Cellular Homeostasis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066CX, The Netherlands .,Leeuwenhoek Centre for Advanced Microscopy (LCAM), Molecular Cytology section at Swammerdam Institute for Life Sciences (SILS) at University of Amsterdam, Amsterdam 1066CX, The Netherlands
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48
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Mishra BH, Mishra PP, Raitoharju E, Marttila S, Mononen N, Sievänen H, Viikari J, Juonala M, Laaksonen M, Hutri-Kähönen N, Kähönen M, Raitakari OT, Lehtimäki T. Modular genome-wide gene expression architecture shared by early traits of osteoporosis and atherosclerosis in the Young Finns Study. Sci Rep 2021; 11:7111. [PMID: 33782480 PMCID: PMC8007808 DOI: 10.1038/s41598-021-86536-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 03/12/2021] [Indexed: 02/07/2023] Open
Abstract
We analysed whole blood genome-wide expression data to identify gene co-expression modules shared by early traits of osteoporosis and atherosclerosis. Gene expression was profiled for the Young Finns Study participants. Bone mineral density and content were measured as early traits of osteoporosis. Carotid and bulbus intima media thickness were measured as early traits of atherosclerosis. Joint association of the modules, identified with weighted co-expression analysis, with early traits of the diseases was tested with multivariate analysis. Among the six modules significantly correlated with early traits of both the diseases, two had significant (adjusted p-values (p.adj) < 0.05) and another two had suggestively significant (p.adj < 0.25) joint association with the two diseases after adjusting for age, sex, body mass index, smoking habit, alcohol consumption, and physical activity. The three most significant member genes from the significant modules were NOSIP, GXYLT2, and TRIM63 (p.adj ≤ 0.18). Genes in the modules were enriched with biological processes that have separately been found to be involved in either bone metabolism or atherosclerosis. The gene modules and their most significant member genes identified in this study support the osteoporosis-atherosclerosis comorbidity hypothesis and can provide new joint biomarkers for both diseases and their dual prevention.
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Affiliation(s)
- Binisha H Mishra
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
| | - Pashupati P Mishra
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
| | - Emma Raitoharju
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
| | - Saara Marttila
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
- Gerontology Research Center (GEREC), Tampere University, Tampere, Finland
| | - Nina Mononen
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
| | - Harri Sievänen
- The UKK Institute for Health Promotion Research, Tampere, Finland
| | - Jorma Viikari
- Department of Medicine, University of Turku, Turku, Finland
- Division of Medicine, Turku University Hospital, Turku, Finland
| | - Markus Juonala
- Department of Medicine, University of Turku, Turku, Finland
- Division of Medicine, Turku University Hospital, Turku, Finland
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
| | | | - Nina Hutri-Kähönen
- Department of Paediatrics, Tampere University Hospital, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Mika Kähönen
- Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
| | - Olli T Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
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49
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Johnston RJ, Lee PS, Strop P, Smyth MJ. Cancer Immunotherapy and the Nectin Family. ANNUAL REVIEW OF CANCER BIOLOGY-SERIES 2021. [DOI: 10.1146/annurev-cancerbio-060920-084910] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
It is increasingly clear that the nectin family and its immunoreceptors shape the immune response to cancer through several pathways. Yet, even as antibodies against TIGIT, CD96, and CD112R advance into clinical development, biological and therapeutic questions remain unanswered. Here, we review recent progress, prospects, and challenges to understanding and tapping this family in cancer immunotherapy.
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Affiliation(s)
- Robert J. Johnston
- Oncology Discovery, Bristol Myers Squibb, Redwood City, California 94063, USA
| | - Peter S. Lee
- Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, California 94063, USA;,
| | - Pavel Strop
- Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, California 94063, USA;,
| | - Mark J. Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
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50
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CD112 Regulates Angiogenesis and T Cell Entry into the Spleen. Cells 2021; 10:cells10010169. [PMID: 33467729 PMCID: PMC7830896 DOI: 10.3390/cells10010169] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 12/19/2022] Open
Abstract
Junctional adhesion proteins play important roles in controlling angiogenesis, vascular permeability and leukocyte trafficking. CD112 (nectin-2) belongs to the immunoglobulin superfamily and was shown to engage in homophilic and heterophilic interactions with a variety of binding partners expressed on endothelial cells and on leukocytes. Recent in vitro studies suggested that CD112 regulates human endothelial cell migration and proliferation as well as transendothelial migration of leukocytes. However, so far, the role of CD112 in endothelial cell biology and in leukocyte trafficking has not been elucidated in vivo. We found CD112 to be expressed by lymphatic and blood endothelial cells in different murine tissues. In CD112-deficient mice, the blood vessel coverage in the retina and spleen was significantly enhanced. In functional in vitro studies, a blockade of CD112 modulated endothelial cell migration and significantly enhanced endothelial tube formation. An antibody-based blockade of CD112 also significantly reduced T cell transmigration across endothelial monolayers in vitro. Moreover, T cell homing to the spleen was significantly reduced in CD112-deficient mice. Overall, our results identify CD112 as a regulator of angiogenic processes in vivo and demonstrate a novel role for CD112 in T cell entry into the spleen.
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