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Dong D, Yu X, Liu H, Xu J, Guo J, Guo W, Li X, Wang F, Zhang D, Liu K, Sun Y. Study of immunosenescence in the occurrence and immunotherapy of gastrointestinal malignancies. Semin Cancer Biol 2025; 111:16-35. [PMID: 39929408 DOI: 10.1016/j.semcancer.2025.01.007] [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: 12/15/2024] [Revised: 01/18/2025] [Accepted: 01/26/2025] [Indexed: 02/25/2025]
Abstract
In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.
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Affiliation(s)
- Daosong Dong
- Department of Pain, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xue Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Molecular Pathology and Epidemiology of Gastric Cancer in the Universities of Liaoning Province, Shenyang, Liaoning 110001, China
| | - Haoran Liu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Jingjing Xu
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Jiayan Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiang Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Fei Wang
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Dongyong Zhang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Kaiwei Liu
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Yanbin Sun
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang 110001, China.
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2
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Keshavarz Sadegh R, Saleki K, Rezaei N. Immune checkpoint inhibitor (ICI) therapy in central nervous system cancers: State-of-the-art and future outlook. Int Immunopharmacol 2025; 159:114837. [PMID: 40394797 DOI: 10.1016/j.intimp.2025.114837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 04/28/2025] [Accepted: 05/07/2025] [Indexed: 05/22/2025]
Abstract
Invasive central nervous system (CNS) cancers are an area where the development of breakthrough therapies is urgently needed. For instance, conditions such as glioblastoma multiforme (GBM) are associated with poor clinical prognosis, with the majority of trials offering no improvement to marginally enhanced survival. Unleashing the potential of targeting the immune system in CNS cancers has gained attention in recent years. Inhibition of immune checkpoints such as CTLA-4, PD-1/PD-L1, TIM-3, and LAG-3 has been attempted in recent trials. While potentially offering a notable edge over other immunotherapies, multi-organ adverse events have been found with the administration of immune checkpoint inhibitors (ICIs). The present review captures the state-of-the-art evidence on ICI treatments in different CNS cancers. Also, we discuss the value of combinational therapies involving ICIs as well as next-generation therapeutics such as bispecific antibodies targeting PD-1/LAG-3/TIM-3 and CRISPR-Cas9-edited PD-1-knock-out checkpoint-resistant CAR T-cells.
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Affiliation(s)
- Roghaye Keshavarz Sadegh
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Kiarash Saleki
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN MUBabol Office, Universal Scientific Education and Research Network (USERN), Babol, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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3
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Kim Y, Panda AK, Shevach EM. Treg Control of CD80/CD86 Expression Mediates Immune System Homeostasis. Eur J Immunol 2025; 55:e202551771. [PMID: 40346769 PMCID: PMC12064877 DOI: 10.1002/eji.202551771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 04/04/2025] [Accepted: 04/09/2025] [Indexed: 05/12/2025]
Abstract
Foxp3+ regulatory T cells (Treg) are critical for the maintenance of self-tolerance, and their absence or dysfunction can result in autoimmunity. To determine the critical cell type controlled by Treg and potentially the suppressor mechanism utilized by Treg in the steady state, we utilized mice expressing the diphtheria toxin receptor (DTR) exclusively on Treg cells. Complete depletion of Treg was achieved 24 h after DT treatment, but profound activation of CD4+ and CD8+ T cells as measured by induction of CD44 expression and proliferation required 3-4 days. Increased expression of CD80/CD86 was observed on dendritic cells and more prominently on macrophages after 3 days. Depletion of CD4+ T cells or macrophages resulted in ∼50% inhibition of T-cell activation. The initial steps in T-cell activation were completely independent of IFN-γ or IL-2, while upregulation of CD80/CD86 was partially dependent on IFN-γ. Complete reversal of immune activation post-Treg depletion was only achieved by blockade of CD80/CD86 interactions with CD28. We conclude that the major mechanism used by Treg in the steady state is the regulation of CD80/CD86 expression and dysregulation of this suppressor pathway results in lethal autoimmunity driven by co-stimulatory signals in concert with TCR stimulation, or even by costimulatory signals alone.
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Affiliation(s)
- Yong‐Hee Kim
- Cellular Immunology SectionLaboratory of Immune System BiologyNational Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaMarylandUSA
| | - Abir K. Panda
- Cellular Immunology SectionLaboratory of Immune System BiologyNational Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaMarylandUSA
| | - Ethan M. Shevach
- Cellular Immunology SectionLaboratory of Immune System BiologyNational Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaMarylandUSA
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4
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Chalepaki AM, Gkoris M, Chondrou I, Kourti M, Georgakopoulos-Soares I, Zaravinos A. A multi-omics analysis of effector and resting treg cells in pan-cancer. Comput Biol Med 2025; 189:110021. [PMID: 40088713 DOI: 10.1016/j.compbiomed.2025.110021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 02/09/2025] [Accepted: 03/11/2025] [Indexed: 03/17/2025]
Abstract
Regulatory T cells (Tregs) are critical for maintaining the stability of the immune system and facilitating tumor escape through various mechanisms. Resting T cells are involved in cell-mediated immunity and remain in a resting state until stimulated, while effector T cells promote immune responses. Here, we investigated the roles of two gene signatures, one for resting Tregs (FOXP3 and IL2RA) and another for effector Tregs (FOXP3, CTLA-4, CCR8 and TNFRSF9) in pan-cancer. Using data from The Cancer Genome Atlas (TCGA), The Cancer Proteome Atlas (TCPA) and Gene Expression Omnibus (GEO), we focused on the expression profile of the two signatures, the existence of single nucleotide variants (SNVs) and copy number variants (CNVs), methylation, infiltration of immune cells in the tumor and sensitivity to different drugs. Our analysis revealed that both signatures are differentially expressed across different cancer types, and correlate with patient survival. Furthermore, both types of Tregs influence important pathways in cancer development and progression, like apoptosis, epithelial-to-mesenchymal transition (EMT) and the DNA damage pathway. Moreover, a positive correlation was highlighted between the expression of gene markers in both resting and effector Tregs and immune cell infiltration in adrenocortical carcinoma, while mutations in both signatures correlated with enrichment of specific immune cells, mainly in skin melanoma and endometrial cancer. In addition, we reveal the existence of widespread CNVs and hypomethylation affecting both Treg signatures in most cancer types. Last, we identified a few correlations between the expression of CCR8 and TNFRSF9 and sensitivity to several drugs, including COL-3, Chlorambucil and GSK1070916, in pan-cancer. Overall, these findings highlight new evidence that both Treg signatures are crucial regulators of cancer progression, providing potential clinical outcomes for cancer therapy.
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Affiliation(s)
- Anna-Maria Chalepaki
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
| | - Marios Gkoris
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
| | - Irene Chondrou
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.
| | - Malamati Kourti
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.
| | - Ilias Georgakopoulos-Soares
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
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5
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Ren J, Yan G, Yang L, Kong L, Guan Y, Sun H, Liu C, Liu L, Han Y, Wang X. Cancer chemoprevention: signaling pathways and strategic approaches. Signal Transduct Target Ther 2025; 10:113. [PMID: 40246868 PMCID: PMC12006474 DOI: 10.1038/s41392-025-02167-1] [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: 08/02/2024] [Revised: 12/01/2024] [Accepted: 02/04/2025] [Indexed: 04/19/2025] Open
Abstract
Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.
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Affiliation(s)
- Junling Ren
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Guangli Yan
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Le Yang
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China
| | - Ling Kong
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Yu Guan
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Hui Sun
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
| | - Chang Liu
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Lei Liu
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Ying Han
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Xijun Wang
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China.
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6
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Osaki M, Sakaguchi S. Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity. Immunity 2025; 58:889-908.e13. [PMID: 40168991 DOI: 10.1016/j.immuni.2025.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 10/29/2024] [Accepted: 03/05/2025] [Indexed: 04/03/2025]
Abstract
Cytotoxic T-lymphocyte-associated antigen -4 (CTLA-4) is a co-inhibitory receptor that restricts T cell activation. CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms, but the key producers, kinetics, and functions of sCTLA-4 are unclear. Here, we investigated the roles of sCTLA-4 in immune regulation under non-inflammatory and inflammatory conditions. Effector regulatory T (Treg) cells were the most active sCTLA-4 producers in basal and inflammatory states, with distinct kinetics upon T cell receptor (TCR) stimulation. We generated mice specifically deficient in sCTLA-4 production, which exhibited spontaneous activation of type 1 immune cells and heightened autoantibody/immunoglobulin E (IgE) production. Conversely, mCTLA-4-deficient mice developed severe type 2-skewed autoimmunity. sCTLA-4 blockade of CD80/86 on antigen-presenting cells inhibited T helper (Th)1, but not Th2, differentiation in vitro. In vivo, Treg-produced sCTLA-4, suppressed Th1-mediated experimental colitis, and enhanced wound healing but hampered tumor immunity. Thus, sCTLA-4 is essential for immune homeostasis and controlling type 1 immunity while allowing type 2 immunity to facilitate resolution in inflammatory conditions.
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Affiliation(s)
- Motonao Osaki
- Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Experimental Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Experimental Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
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7
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Liu S, Liu C, He Y, Li J. Benign non-immune cells in tumor microenvironment. Front Immunol 2025; 16:1561577. [PMID: 40248695 PMCID: PMC12003390 DOI: 10.3389/fimmu.2025.1561577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 02/24/2025] [Indexed: 04/19/2025] Open
Abstract
The tumor microenvironment (TME) is a highly complex and continuous evolving ecosystem, consisting of a diverse array of cellular and non-cellular components. Among these, benign non-immune cells, including cancer-associated fibroblasts (CAFs), adipocytes, endothelial cells (ECs), pericytes (PCs), Schwann cells (SCs) and others, are crucial factors for tumor development. Benign non-immune cells within the TME interact with both tumor cells and immune cells. These interactions contribute to tumor progression through both direct contact and indirect communication. Numerous studies have highlighted the role that benign non-immune cells exert on tumor progression and potential tumor-promoting mechanisms via multiple signaling pathways and factors. However, these benign non-immune cells may play different roles across cancer types. Therefore, it is important to understand the potential roles of benign non-immune cells within the TME based on tumor heterogeneity. A deep understanding allows us to develop novel cancer therapies by targeting these cells. In this review, we will introduce several types of benign non-immune cells that exert on different cancer types according to tumor heterogeneity and their roles in the TME.
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Affiliation(s)
- Shaowen Liu
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chunhui Liu
- The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Yuan He
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jun Li
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
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Choi SH, Chen YW, Panian J, Yuen K, McKay RR. Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma. Oncologist 2025; 30:oyae276. [PMID: 39401004 PMCID: PMC11954509 DOI: 10.1093/oncolo/oyae276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/10/2024] [Indexed: 10/15/2024] Open
Abstract
Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14 390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.
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Affiliation(s)
- Sharon H Choi
- Division of Hematology Oncology, University of California San Diego, San Diego, CA, United States
| | - Yu-Wei Chen
- Division of Hematology Oncology, University of California San Diego, San Diego, CA, United States
| | - Justine Panian
- Division of Hematology Oncology, University of California San Diego, San Diego, CA, United States
| | - Kit Yuen
- Department of Urology, University of California San Diego, San Diego, CA, United States
| | - Rana R McKay
- Division of Hematology Oncology, University of California San Diego, San Diego, CA, United States
- Department of Urology, University of California San Diego, San Diego, CA, United States
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Sharafi Monfared M, Nazmi S, Parhizkar F, Jafari D. Soluble B7 and TNF family in colorectal cancer: Serum level, prognostic and treatment value. Hum Immunol 2025; 86:111232. [PMID: 39793378 DOI: 10.1016/j.humimm.2025.111232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/25/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025]
Abstract
Soluble immune checkpoints (sIC) are crucial factors in the immune system. They regulate immune responses by transforming intercellular signals via binding to their membrane-bound receptor or ligand. Moreover, soluble ICs are vital in immune regulation, cancer development, and prognosis. They can be identified and measured in various tumor microenvironments. Recently, sICs have become increasingly important in clinically assessing malignancies like colorectal cancer (CRC) patients. This review explores the evolving role of the soluble B7 family and soluble tumor necrosis factor (TNF) superfamily members in predicting disease progression, treatment response, and overall patient outcomes in CRC. We comprehensively analyze the diagnostic and prognostic potential of soluble immune checkpoints in CRC. Understanding the role of these soluble immune checkpoints in CRC management and their potential as targets for precision medicine approaches can be critical for improving outcomes for patients with colorectal cancer.
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Affiliation(s)
- Mohanna Sharafi Monfared
- Student's Research Committee, Zanjan University of Medical Sciences, Zanjan, Iran; School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Sina Nazmi
- Student's Research Committee, Zanjan University of Medical Sciences, Zanjan, Iran; School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Forough Parhizkar
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
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Giesler S, Riemer R, Lowinus T, Zeiser R. Immune-mediated colitis after immune checkpoint inhibitor therapy. Trends Mol Med 2025; 31:265-280. [PMID: 39477757 DOI: 10.1016/j.molmed.2024.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/23/2024] [Accepted: 09/30/2024] [Indexed: 03/15/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.
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Affiliation(s)
- Sophie Giesler
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roxane Riemer
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Theresa Lowinus
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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Abdo EL, Ajib I, El Mounzer J, Husseini M, Kalaoun G, Matta TM, Mosleh R, Nasr F, Richani N, Khalil A, Shayya A, Ghanem H, Faour WH. Molecular biology of the novel anticancer medications: a focus on kinases inhibitors, biologics and CAR T-cell therapy. Inflamm Res 2025; 74:41. [PMID: 39960501 DOI: 10.1007/s00011-025-02008-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 01/28/2025] [Accepted: 02/10/2025] [Indexed: 05/09/2025] Open
Abstract
INTRODUCTION Cancer treatment underwent significant changes in the last few years with the introduction of novel treatments targeting the immune system. OBJECTIVES The objective of this review is to discuss novel anticancer drugs including kinase inhibitors, biologics and cellular therapy with CAR-T cells. METHODS Most recent research articles were extracted from PubMed using keywords such as "kinases inhibitors", "CAR-T cell therapy". RESULTS AND DISCUSSION The number of kinase inhibitors is significantly increasing due to their demonstrated effectiveness in combination with biologics. CAR-T represented a major breakthrough in the field. Also, it focused on their mechanisms of action and the rational of their use either alone or in combination in relation to their modes of action.
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Affiliation(s)
- Elia-Luna Abdo
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Imad Ajib
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Jason El Mounzer
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Mohammad Husseini
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Gharam Kalaoun
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Tatiana-Maria Matta
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Reine Mosleh
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Fidel Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Nour Richani
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Anwar Shayya
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
- Department of Hematology-Oncology, Lebanese American University Medical Center- Rizk Hospital, Beirut, Lebanon
| | - Hady Ghanem
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
- Department of Hematology-Oncology, Lebanese American University Medical Center- Rizk Hospital, Beirut, Lebanon
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon.
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12
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Søndergaard JN, Tulyeu J, Priest D, Sakaguchi S, Wing JB. Single cell suppression profiling of human regulatory T cells. Nat Commun 2025; 16:1325. [PMID: 39900891 PMCID: PMC11791207 DOI: 10.1038/s41467-024-55746-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 12/23/2024] [Indexed: 02/05/2025] Open
Abstract
Regulatory T cells (Treg) play an important role in regulating immune homeostasis in health and disease. Traditionally their suppressive function has been assayed by mixing purified cell populations, which does not provide an accurate picture of a physiologically relevant response. To overcome this limitation, we here develop 'single cell suppression profiling of human Tregs' (scSPOT). scSPOT uses a 52-marker CyTOF panel, a cell division detection algorithm, and a whole PBMC system to assess the effect of Tregs on all other cell types simultaneously. In this head-to-head comparison, we find Tregs having the clearest suppressive effects on effector memory CD8 T cells through partial division arrest, cell cycle inhibition, and effector molecule downregulation. Additionally, scSPOT identifies a Treg phenotypic split previously observed in viral infection and propose modes of action by the FDA-approved drugs Ipilimumab and Tazemetostat. scSPOT is thus scalable, robust, widely applicable, and may be used to better understand Treg immunobiology and screen for therapeutic compounds.
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Affiliation(s)
- Jonas Nørskov Søndergaard
- Human Immunology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan.
| | - Janyerkye Tulyeu
- Human Immunology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan
| | - David Priest
- Laboratory of Human Single Cell Immunology, WPI-IFReC, Osaka University, Suita, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, WPI-IFReC, Osaka University, Suita, Japan
- Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - James B Wing
- Human Immunology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan.
- Laboratory of Human Single Cell Immunology, WPI-IFReC, Osaka University, Suita, Japan.
- Center for Advanced Modalities and DDS (CAMaD), Osaka University, Osaka, Japan.
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13
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Sun Z, Wu Z, Su X. Developing an Effective Therapeutic HPV Vaccine to Eradicate Large Tumors by Genetically Fusing Xcl1 and Incorporating IL-9 as Molecular Adjuvants. Vaccines (Basel) 2025; 13:49. [PMID: 39852828 PMCID: PMC11768903 DOI: 10.3390/vaccines13010049] [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: 12/11/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/26/2025] Open
Abstract
BACKGROUND Human papillomavirus (HPV) is a prevalent infection affecting both men and women, leading to various cytological lesions. Therapeutic vaccines mount a HPV-specific CD8+ cytotoxic T lymphocyte response, thus clearing HPV-infected cells. However, no therapeutic vaccines targeting HPV are currently approved for clinical treatment due to limited efficacy. Our goal is to develop a vaccine that can effectively eliminate tumors caused by HPV. METHODS We genetically fused the chemokine XCL1 with the E6 and E7 proteins of HPV16 to target cDC1 and enhance the vaccine-induced cytotoxic T cell response, ultimately developing a DNA vaccine. Additionally, we screened various interleukins and identified IL-9 as an effective molecular adjuvant for our DNA vaccine. RESULTS The fusion of Xcl1 significantly improved the quantity and quality of the specific CD8+ T cells. The fusion of Xcl1 also increased immune cell infiltration into the tumor microenvironment. The inclusion of IL-9 significantly elevated the vaccine-induced specific T cell response and enhanced anti-tumor efficacy. IL-9 promotes the formation of central memory T cells. CONCLUSIONS the fusion of Xcl1 and the use of IL-9 as a molecular adjuvant represent promising strategies for vaccine development.
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Affiliation(s)
- Zhongjie Sun
- State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
- Newish Biological R&D Center, Wuxi 214111, China
| | - Zhongyan Wu
- Newish Biological R&D Center, Wuxi 214111, China
| | - Xuncheng Su
- State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
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14
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Tey PY, Dufner A, Knobeloch KP, Pruneda JN, Clague MJ, Urbé S. Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation. J Cell Biol 2025; 224:e202312141. [PMID: 39404738 PMCID: PMC11486831 DOI: 10.1083/jcb.202312141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 08/14/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
The immune checkpoint regulator CTLA4 is an unusually short-lived membrane protein. Here, we show that its lysosomal degradation is dependent on ubiquitylation at lysine residues 203 and 213. Inhibition of the v-ATPase partially restores CTLA4 levels following cycloheximide treatment, but also reveals a fraction that is secreted in exosomes. The endosomal deubiquitylase, USP8, interacts with CTLA4, and its loss enhances CTLA4 ubiquitylation in cancer cells, mouse CD4+ T cells, and cancer cell-derived exosomes. Depletion of the USP8 adapter protein, HD-PTP, but not ESCRT-0 recapitulates this cellular phenotype but shows distinct properties vis-à-vis exosome incorporation. Re-expression of wild-type USP8, but neither a catalytically inactive nor a localization-compromised ΔMIT domain mutant can rescue delayed degradation of CTLA4 or counteract its accumulation in clustered endosomes. UbiCRest analysis of CTLA4-associated ubiquitin chain linkages identifies a complex mixture of conventional Lys63- and more unusual Lys27- and Lys29-linked polyubiquitin chains that may underly the rapidity of protein turnover.
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Affiliation(s)
- Pei Yee Tey
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Almut Dufner
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Klaus-Peter Knobeloch
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Jonathan N. Pruneda
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, USA
| | - Michael J. Clague
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Sylvie Urbé
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
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15
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Pandey H, Tang DWT, Wong SH, Lal D. Helminths in alternative therapeutics of inflammatory bowel disease. Intest Res 2025; 23:8-22. [PMID: 39916482 PMCID: PMC11834367 DOI: 10.5217/ir.2023.00059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 10/24/2023] [Accepted: 11/01/2023] [Indexed: 02/20/2025] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a nonspecific chronic inflammation of the gastrointestinal tract. Despite recent advances in therapeutics and newer management strategies, IBD largely remains untreatable. Helminth therapy is a promising alternative therapeutic for IBD that has gained some attention in the last two decades. Helminths have immunomodulatory effects and can alter the gut microbiota. The immunomodulatory effects include a strong Th2 immune response, T-regulatory cell response, and the production of regulatory cytokines. Although concrete evidence regarding the efficacy of helminth therapy in IBD is lacking, clinical studies and studies done in animal models have shown some promise. Most clinical studies have shown that helminth therapy is safe and easily tolerable. Extensive work has been done on the whipworm Trichuris, but other helminths, including Schistosoma, Trichinella, Heligmosomoides, and Ancylostoma, have also been explored for pre-clinical and animal studies. This review article summarizes the potential of helminth therapy as an alternative therapeutic or an adjuvant to the existing therapeutic procedures for IBD treatment.
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Affiliation(s)
| | - Daryl W. T. Tang
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Sunny H. Wong
- Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Devi Lal
- Department of Zoology, Ramjas College, University of Delhi, Delhi, India
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16
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Pandit A, Shah SM, Shah RA, Qureshi S, Sethi RS, Bhat F, Malik A, Parray O, Yaqoob H, Saleem M. Regulatory T cells in bovine fertility: Current understanding and future prospects. Anim Reprod Sci 2025; 272:107655. [PMID: 39616725 DOI: 10.1016/j.anireprosci.2024.107655] [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: 05/26/2024] [Revised: 09/17/2024] [Accepted: 11/24/2024] [Indexed: 12/20/2024]
Abstract
Regulatory T cells (Tregs) have emerged as crucial players in maintaining maternal-fetal tolerance and promoting successful pregnancy outcomes. This review examines the importance of these cells in pregnancy, drawing on human and animal-based studies, with a focus on their role in bovine fertility. Tregs employ various mechanisms to mediate maternal-fetal tolerance, including regulation of effector T-cell responses, interactions with innate immune cells in the uterine microenvironment, and modulation of trophoblast function. In humans, Treg dynamics during normal pregnancy and alterations in pregnancy complications provide compelling evidence for their involvement in maintaining fetal-maternal harmony. Animal models, particularly mouse studies, have further elucidated the importance of Tregs in preventing fetal rejection and promoting successful pregnancy outcomes. The review also explores the characterization of bovine Tregs, highlighting their similarities and unique features compared to human and rodent counterparts. Recent studies have indicated the presence and potential significance of Tregs in the bovine uterine environment during early pregnancy. Translational applications of Treg research in livestock fertility are discussed, with a focus on immunomodulatory strategies for enhancing Treg function, such as antigen-specific tolerance induction, pharmacological targeting of Treg pathways, and cell-based therapies using autologous or allogeneic Tregs. The review concludes by emphasizing the potential impact of Treg-based strategies on the livestock industry and the broader implications for human reproductive health. Future research directions are outlined, underscoring the need for further investigations into the role of Tregs in bovine reproductive tissues and their relationship with fertility outcomes.
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Affiliation(s)
- Arif Pandit
- Center of Excellence in Animal Reproductive Biotechnology, Mountain Livestock Research Institute, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India.
| | - Syed M Shah
- Center of Excellence in Animal Reproductive Biotechnology, Mountain Livestock Research Institute, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Riaz A Shah
- Center of Excellence in Animal Reproductive Biotechnology, Mountain Livestock Research Institute, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Sabia Qureshi
- Division of Veterinary Microbiology and Immunology, Faculty of Veterinary Sciences, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India
| | - R S Sethi
- College of Dairy Sciences, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, Punjab, India
| | - Faheem Bhat
- Center of Excellence in Animal Reproductive Biotechnology, Mountain Livestock Research Institute, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Abrar Malik
- Center of Excellence in Animal Reproductive Biotechnology, Mountain Livestock Research Institute, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Oveas Parray
- Center of Excellence in Animal Reproductive Biotechnology, Mountain Livestock Research Institute, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Hilal Yaqoob
- Center of Excellence in Animal Reproductive Biotechnology, Mountain Livestock Research Institute, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Masood Saleem
- Directorate of Research, Sher E Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India.
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17
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Maruyama S, Imamura Y, Toihata T, Haraguchi I, Takamatsu M, Yamashita M, Nakashima Y, Oki E, Taguchi K, Yamamoto M, Mine S, Okamura A, Kanamori J, Nunobe S, Sano T, Kitano S, Noda T, Watanabe M. FOXP3+/CD8+ ratio associated with aggressive behavior in RUNX3-methylated diffuse esophagogastric junction tumor. Cancer Sci 2025; 116:178-191. [PMID: 39440906 PMCID: PMC11711055 DOI: 10.1111/cas.16373] [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: 06/05/2024] [Revised: 09/21/2024] [Accepted: 10/03/2024] [Indexed: 10/25/2024] Open
Abstract
The tumor immune microenvironment is increasingly becoming a key consideration in developing treatment regimens for aggressive cancers, with evidence that regulatory T cells (Tregs) attenuate the antitumor response by interrupting cytotoxic T cells (CD8+). Here, we hypothesized the prognostic relevance of the proportions of Tregs (marked by forkhead box protein 3 [FOXP3]) and CD8+ cells in diffuse, non-Epstein-Barr virus (EBV)/non-microsatellite instability (MSI)-high gastroesophageal adenocarcinomas (GEAs), which are clinically characterized as more aggressive, immunologically inactive tumors as compared with their intestinal counterparts. Cell-count ratios of FOXP3+/CD8+ expression were calculated at the intratumoral region and invasive margin discretely on digital images from 303 chemo-naive non-EBV/non-MSI-high esophagogastric junction (EGJ) adenocarcinomas. A significant modifying prognostic effect of tumor histology was observed between 5-year EGJ cancer-specific survival and the FOXP3+/CD8+ ratio at the invasive margin in pStage I-III tumors (p for interaction = 0.022; hazard ratio [HR] = 8.47 and 95% confidence interval [CI], 2.04-35.19 for high ratio [vs. low] for diffuse; HR = 1.57 and 95% CI, 0.88-2.83 for high ratio [vs. low] for intestinal). A high FOXP3+/CD8+ ratio at the invasive margin was associated with RUNX3 methylation (p = 0.035) and poor prognosis in RUNX3-methylated diffuse histological subtype (5-year EGJ cancer-specific survival, 52.3% for high and 100% for low, p = 0.015). Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3-suppressed diffuse histological subtypes of non-EBV/non-MSI-high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3-methylated diffuse histological subtype.
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Affiliation(s)
- Suguru Maruyama
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yu Imamura
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tasuku Toihata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Ikumi Haraguchi
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Manabu Takamatsu
- Department of Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Makiko Yamashita
- Advanced Medical Development Center, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuichiro Nakashima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichi Taguchi
- Department of Pathology, Kyushu Cancer Center, National Hospital Organization, Fukuoka, Japan
| | - Manabu Yamamoto
- Department of Gastroenterological Surgery, Kyushu Cancer Center, National Hospital Organization, Fukuoka, Japan
| | - Shinji Mine
- Department of Esophageal and Gastroenterological Surgery, Juntendo University Hospital, Tokyo, Japan
| | - Akihiko Okamura
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Jun Kanamori
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Souya Nunobe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeshi Sano
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shigehisa Kitano
- Advanced Medical Development Center, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuo Noda
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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18
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Wolf S, Madanchi M, Turko P, Hollmén M, Tugues S, von Atzigen J, Giovanoli P, Dummer R, Lindenblatt N, Halin C, Detmar M, Levesque M, Gousopoulos E. Anti-CTLA4 treatment reduces lymphedema risk potentially through a systemic expansion of the FOXP3 + T reg population. Nat Commun 2024; 15:10784. [PMID: 39737964 PMCID: PMC11686037 DOI: 10.1038/s41467-024-55002-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/27/2024] [Indexed: 01/01/2025] Open
Abstract
Secondary lymphedema is a common sequel of oncologic surgery and presents a global health burden still lacking pharmacological treatment. The infiltration of the lymphedematous extremities with CD4+T cells influences lymphedema onset and emerges as a promising therapy target. Here, we show that the modulation of CD4+FOXP3+CD25+regulatory T (Treg) cells upon anti-CTLA4 treatment protects against lymphedema development in patients with melanoma and in a mouse lymphedema model. A retrospective evaluation of a melanoma patient registry reveals that anti-CTLA4 reduces lymphedema risk; in parallel, anti-CTLA4 reduces edema and improves lymphatic function in a mouse-tail lymphedema model. This protective effect of anti-CTLA4 correlates with a systemic expansion of Tregs, both in the animal model and in patients with melanoma. Our data thus show that anti-CTLA4 with its lymphedema-protective and anti-tumor properties is a promising candidate for more diverse application in the clinics.
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Affiliation(s)
- Stefan Wolf
- Division of Plastic Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Matiar Madanchi
- Division of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Patrick Turko
- Division of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Bioinformatic Department, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Maija Hollmén
- MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Sonia Tugues
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Julia von Atzigen
- Division of Plastic Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Pietro Giovanoli
- Division of Plastic Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Reinhard Dummer
- Division of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Nicole Lindenblatt
- Division of Plastic Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Cornelia Halin
- Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland
| | - Mitchell Levesque
- Division of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Epameinondas Gousopoulos
- Division of Plastic Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
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19
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Eshaq AM, Flanagan TW, Ba Abbad AA, Makarem ZAA, Bokir MS, Alasheq AK, Al Asheikh SA, Almashhor AM, Binyamani F, Al-Amoudi WA, Bawzir AS, Haikel Y, Megahed M, Hassan M. Immune Checkpoint Inhibitor-Associated Cutaneous Adverse Events: Mechanisms of Occurrence. Int J Mol Sci 2024; 26:88. [PMID: 39795946 PMCID: PMC11719825 DOI: 10.3390/ijms26010088] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
Immunotherapy, particularly that based on blocking checkpoint proteins in many tumors, including melanoma, Merkel cell carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast (TNB cancer), renal cancer, and gastrointestinal and endometrial neoplasms, is a therapeutic alternative to chemotherapy. Immune checkpoint inhibitor (ICI)-based therapies have the potential to target different pathways leading to the destruction of cancer cells. Although ICIs are an effective treatment strategy for patients with highly immune-infiltrated cancers, the development of different adverse effects including cutaneous adverse effects during and after the treatment with ICIs is common. ICI-associated cutaneous adverse effects include mostly inflammatory and bullous dermatoses, as well as severe cutaneous side reactions such as rash or inflammatory dermatitis encompassing erythema multiforme; lichenoid, eczematous, psoriasiform, and morbilliform lesions; and palmoplantar erythrodysesthesia. The development of immunotherapy-related adverse effects is a consequence of ICIs' unique molecular action that is mainly mediated by the activation of cytotoxic CD4+/CD8+ T cells. ICI-associated cutaneous disorders are the most prevalent effects induced in response to anti-programmed cell death 1 (PD-1), anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and anti-programmed cell death ligand 1 (PD-L1) agents. Herein, we will elucidate the mechanisms regulating the occurrence of cutaneous adverse effects following treatment with ICIs.
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Affiliation(s)
- Abdulaziz M. Eshaq
- Department of Epidemiology and Biostatstics, Milken Institute School of Public Health, George Washington University Washington, Washington, DC 20052, USA;
- Research Laboratory of Surgery-Oncology, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Thomas W. Flanagan
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA;
| | - Abdulqader A. Ba Abbad
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (A.A.B.A.); (Z.A.A.M.); (M.S.B.); (A.K.A.); (A.M.A.); (F.B.); (W.A.A.-A.)
| | - Zain Alabden A. Makarem
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (A.A.B.A.); (Z.A.A.M.); (M.S.B.); (A.K.A.); (A.M.A.); (F.B.); (W.A.A.-A.)
| | - Mohammed S. Bokir
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (A.A.B.A.); (Z.A.A.M.); (M.S.B.); (A.K.A.); (A.M.A.); (F.B.); (W.A.A.-A.)
| | - Ahmed K. Alasheq
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (A.A.B.A.); (Z.A.A.M.); (M.S.B.); (A.K.A.); (A.M.A.); (F.B.); (W.A.A.-A.)
| | - Sara A. Al Asheikh
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (A.A.B.A.); (Z.A.A.M.); (M.S.B.); (A.K.A.); (A.M.A.); (F.B.); (W.A.A.-A.)
| | - Abdullah M. Almashhor
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (A.A.B.A.); (Z.A.A.M.); (M.S.B.); (A.K.A.); (A.M.A.); (F.B.); (W.A.A.-A.)
| | - Faroq Binyamani
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (A.A.B.A.); (Z.A.A.M.); (M.S.B.); (A.K.A.); (A.M.A.); (F.B.); (W.A.A.-A.)
| | - Waleed A. Al-Amoudi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (A.A.B.A.); (Z.A.A.M.); (M.S.B.); (A.K.A.); (A.M.A.); (F.B.); (W.A.A.-A.)
| | - Abdulaziz S. Bawzir
- Department of Radiology, King Saud Medical City, Riyadh 11533, Saudi Arabia;
| | - Youssef Haikel
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France;
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
- Pôle de Médecine et Chirurgie Bucco-Dentaire, Hôpital Civil, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France
| | - Mossad Megahed
- Clinic of Dermatology, University Hospital of Aachen, 52074 Aachen, Germany;
| | - Mohamed Hassan
- Research Laboratory of Surgery-Oncology, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France;
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
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20
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Anvari S, Nikbakht M, Vaezi M, Amini-Kafiabad S, Ahmadvand M. Immune checkpoints and ncRNAs: pioneering immunotherapy approaches for hematological malignancies. Cancer Cell Int 2024; 24:410. [PMID: 39702293 DOI: 10.1186/s12935-024-03596-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024] Open
Abstract
Hematological malignancies are typically treated with chemotherapy and radiotherapy as the first-line conventional therapies. However, non-coding RNAs (ncRNAs) are a rapidly expanding field of study in cancer biology that influences the growth, differentiation, and proliferation of tumors by targeting immunological checkpoints. This study reviews the results of studies (from 2012 to 2024) that consider the immune checkpoints and ncRNAs in relation to hematological malignancies receiving immunotherapy. This article provides a summary of the latest advancements in immunotherapy for treating hematological malignancies, focusing on the role of immune checkpoints and ncRNAs in the immune response and their capacity for innovative strategies. The paper also discusses the function of immune checkpoints in maintaining immune homeostasis and how their dysregulation can contribute to developing leukemia and lymphoma. Finally, this research concludes with a discussion on the obstacles and future directions in this rapidly evolving field, emphasizing the need for continued research to fully harness the capacity of immune checkpoints and ncRNAs in immunotherapy for hematological malignancies.
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Affiliation(s)
- Samira Anvari
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mohsen Nikbakht
- Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Vaezi
- Hematology, Oncology, and Stem Cell Transplantation Research Center Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sedigheh Amini-Kafiabad
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran.
| | - Mohammad Ahmadvand
- Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran.
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21
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Hosking SL, Moldenhauer LM, Tran HM, Chan HY, Groome HM, Lovell EA, Green ES, O’Hara SE, Roberts CT, Foyle KL, Davidge ST, Robertson SA, Care AS. Treg cells promote decidual vascular remodeling and modulate uterine NK cells in pregnant mice. JCI Insight 2024; 10:e169836. [PMID: 39656539 PMCID: PMC11790030 DOI: 10.1172/jci.insight.169836] [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: 02/17/2023] [Accepted: 11/26/2024] [Indexed: 01/24/2025] Open
Abstract
Regulatory T (Treg) cells are essential for maternal immune tolerance of the fetus and placenta. In preeclampsia, aberrant Treg cell tolerance is implicated, but how Treg cells affect the uterine vascular dysfunction thought to precede placental impairment and maternal vasculopathy is unclear. We used Foxp3-diphtheria toxin receptor mice to test the hypothesis that Treg cells are essential regulators of decidual spiral artery adaptation to pregnancy. Transient Treg cell depletion during early placental morphogenesis caused impaired remodeling of decidual spiral arteries, altered uterine artery function, and fewer Dolichos biflorus agglutinin+ uterine natural killer (uNK) cells, resulting in late-gestation fetal loss and fetal growth restriction. Replacing the Treg cells by transfer from wild-type donors mitigated the impact on uNK cells, vascular remodeling, and fetal loss. RNA sequencing of decidua revealed genes associated with NK cell function and placental extravillous trophoblasts were dysregulated after Treg cell depletion and normalized by Treg cell replacement. These data implicate Treg cells as essential upstream drivers of uterine vascular adaptation to pregnancy, through a mechanism likely involving phenotypic regulation of uNK cells and trophoblast invasion. The findings provide insight into mechanisms linking impaired adaptive immune tolerance and altered spiral artery remodeling, 2 hallmark features of preeclampsia.
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Affiliation(s)
- Shanna L. Hosking
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Lachlan M. Moldenhauer
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Ha M. Tran
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Hon Y. Chan
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Holly M. Groome
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Evangeline A.K. Lovell
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Ella S. Green
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Stephanie E. O’Hara
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Claire T. Roberts
- Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
| | - Kerrie L. Foyle
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Sandra T. Davidge
- Women and Children’s Health Research Institute, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
| | - Sarah A. Robertson
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Alison S. Care
- Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
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22
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Bulliard Y, Freeborn R, Uyeda MJ, Humes D, Bjordahl R, de Vries D, Roncarolo MG. From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases. Front Immunol 2024; 15:1509956. [PMID: 39697333 PMCID: PMC11653210 DOI: 10.3389/fimmu.2024.1509956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 11/12/2024] [Indexed: 12/20/2024] Open
Abstract
Autoimmune diseases, characterized by the immune system's attack on the body's own tissues, affect millions of people worldwide. Current treatments, which primarily rely on broad immunosuppression and symptom management, are often associated with significant adverse effects and necessitate lifelong therapy. This review explores the next generation of therapies for immune-mediated diseases, including chimeric antigen receptor (CAR) T cell and regulatory T cell (Treg)-based approaches, which offer the prospect of targeted, durable disease remission. Notably, we highlight the emergence of CD19-targeted CAR T cell therapies, and their ability to drive sustained remission in B cell-mediated autoimmune diseases, suggesting a possible paradigm shift. Further, we discuss the therapeutic potential of Type 1 and FOXP3+ Treg and CAR-Treg cells, which aim to achieve localized immune modulation by targeting their activity to specific tissues or cell types, thereby minimizing the risk of generalized immunosuppression. By examining the latest advances in this rapidly evolving field, we underscore the potential of these innovative cell therapies to address the unmet need for long-term remission and potential tolerance induction in individuals with autoimmune and immune-mediated diseases.
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Affiliation(s)
- Yannick Bulliard
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Robert Freeborn
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Molly Javier Uyeda
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Daryl Humes
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Ryan Bjordahl
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - David de Vries
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Maria Grazia Roncarolo
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
- Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
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23
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Nam HJ, Gong JR, Kim YH, Nguyen-Phuong T, Byun N, Yoon JH, Kim YC, Chung H, Lee BH, Kwon H, Lee W, Kang SJ, Park K, Cha B, Kim JI, Kim HJ. Simultaneous Epigenetic and Gene Expression Profiling at Single Cell Resolution Uncovers Stem-Like Treg Subsets Induced With Oligonucleotide Expansion in Humans. Immune Netw 2024; 24:e39. [PMID: 39801740 PMCID: PMC11711129 DOI: 10.4110/in.2024.24.e39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 10/14/2024] [Accepted: 10/17/2024] [Indexed: 01/16/2025] Open
Abstract
Tregs play a central role in maintaining immune tolerance. Recent progress in the clinical application of Tregs underscores their potential for cell therapy. Nevertheless, a notable hurdle remains in producing functional Tregs in vitro. There is also a lack of detailed studies evaluating the function of Tregs during their ex vivo expansion process. Our prior investigation showed that the ex vivo expansion with oligonucleotides produces FoxP3highHelioshigh subsets. To investigate how oligonucleotides in culture media influence on gene expression and epigenetic states at single cell resolution, we sorted Tregs from healthy individuals and profiled in vitro oligonucleotide-expanded and non-expanded Tregs. We discovered a subset of Tregs, specifically enriched in expanded Tregs (seTregs), through oligonucleotide-induced expansion. seTregs showed an enhancement in both stem-like characteristics and functional attributes. Through analysis of histone modification data and gene regulatory networks, we elucidated IKZF2 (Helios) as a pivotal transcription factor in generating these cell subsets. We believe these findings offer insights into evaluating functional regulation of in vitro expanded Tregs aimed at manufacturing Treg-based cell therapies.
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Affiliation(s)
- Hyo Jeong Nam
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jeong-Ryeol Gong
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
| | - Yong-Hee Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Thuy Nguyen-Phuong
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Nari Byun
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea
- Teraimmune, Inc., Gaithersburg, MD 20878, USA
| | | | | | - Hyunwoo Chung
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Brian Hyohyoung Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Haeyoon Kwon
- Department of Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Woochan Lee
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea
| | - Sung-Jun Kang
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Kyunghyuk Park
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea
| | - Bukyoung Cha
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea
| | - Hyun Je Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea
- Department of Dermatology, Seoul National University Hospital, Seoul 03080, Korea
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24
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Yamazaki S. Diverse roles of dendritic cell and regulatory T cell crosstalk in controlling health and disease. Int Immunol 2024; 37:5-14. [PMID: 38953561 DOI: 10.1093/intimm/dxae042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/01/2024] [Indexed: 07/04/2024] Open
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells for lymphocytes, including regulatory T (Treg) cells, a subset of CD4+ T cells expressing CD25 and Foxp3, a transcription factor. Treg cells maintain immunological self-tolerance in mice and humans, and suppress autoimmunity and other various immune responses such as tumor immunity, transplant rejection, allergy, responses to microbes, and inflammation. Treg-cell proliferation is controlled by antigen-presenting DCs. On the other hand, Treg cells suppress the function of DCs by restraining DC maturation. Therefore, the interaction between DCs and Treg cells, DC-Treg crosstalk, could contribute to controlling health and disease. We recently found that unique DC-Treg crosstalk plays a role in several conditions. First, Treg cells are expanded in ultraviolet B (UVB)-exposed skin by interacting with DCs, and the UVB-expanded Treg cells have a healing function. Second, manipulating DC-Treg crosstalk can induce effective acquired immune responses against severe acute respiratory syndrome coronavirus 2 antigens without adjuvants. Third, Treg cells with a special feature interact with DCs in the tumor microenvironment of human head and neck cancer, which may contribute to the prognosis. Understanding the underlying mechanisms of DC-Treg crosstalk may provide a novel strategy to control health and disease.
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Affiliation(s)
- Sayuri Yamazaki
- Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
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25
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Pant A, Jain A, Chen Y, Patel K, Saleh L, Tzeng S, Nitta RT, Zhao L, Wu CYJ, Bederson M, Wang WL, Bergsneider BHL, Choi J, Medikonda R, Verma R, Cho KB, Kim LH, Kim JE, Yazigi E, Lee SY, Rajendran S, Rajappa P, Mackall CL, Li G, Tyler B, Brem H, Pardoll DM, Lim M, Jackson CM. The CCR6-CCL20 Axis Promotes Regulatory T-cell Glycolysis and Immunosuppression in Tumors. Cancer Immunol Res 2024; 12:1542-1558. [PMID: 39133127 DOI: 10.1158/2326-6066.cir-24-0230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/20/2024] [Accepted: 07/24/2024] [Indexed: 08/13/2024]
Abstract
Regulatory T cells (Treg) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity toward CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wild-type mice and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.
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Affiliation(s)
- Ayush Pant
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Aanchal Jain
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yiyun Chen
- Stanford Cancer Institute, Stanford School of Medicine, Stanford, California
| | - Kisha Patel
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Laura Saleh
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Stephany Tzeng
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland
| | - Ryan T Nitta
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Liang Zhao
- Department of Oncology and Medicine, Bloomberg-Kimmel Institute for Immunotherapy, the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Caren Yu-Ju Wu
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Maria Bederson
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - William Lee Wang
- Stanford Cancer Institute, Stanford School of Medicine, Stanford, California
| | | | - John Choi
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Ravi Medikonda
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Rohit Verma
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Kwang Bog Cho
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Lily H Kim
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Jennifer E Kim
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Eli Yazigi
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Si Yeon Lee
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Sakthi Rajendran
- Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Prajwal Rajappa
- Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Crystal L Mackall
- Stanford Cancer Institute, Stanford School of Medicine, Stanford, California
| | - Gordon Li
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Betty Tyler
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Henry Brem
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Drew M Pardoll
- Department of Oncology and Medicine, Bloomberg-Kimmel Institute for Immunotherapy, the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael Lim
- Department of Neurosurgery, Stanford School of Medicine, Palo Alto, California
| | - Christopher M Jackson
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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26
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Lo JW, Schroeder JH, Roberts LB, Mohamed R, Cozzetto D, Beattie G, Omer OS, Ross EM, Heuts F, Jowett GM, Read E, Madgwick M, Neves JF, Korcsmaros T, Jenner RG, Walker LSK, Powell N, Lord GM. CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner. Nat Commun 2024; 15:9520. [PMID: 39496592 PMCID: PMC11535242 DOI: 10.1038/s41467-024-51719-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 05/10/2024] [Indexed: 11/06/2024] Open
Abstract
The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.
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Affiliation(s)
- Jonathan W Lo
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK
| | | | - Luke B Roberts
- School of Immunology and Microbial Sciences, King's College London, London, UK
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Rami Mohamed
- School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Domenico Cozzetto
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK
| | - Gordon Beattie
- CRUK City of London Centre Single Cell Genomics Facility, UCL Cancer Institute, University College London, London, UK
- Genomics Translational Technology Platform, UCL Cancer Institute, University College London, London, UK
| | - Omer S Omer
- School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Ellen M Ross
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection and Immunity, Royal Free Campus, London, UK
| | - Frank Heuts
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection and Immunity, Royal Free Campus, London, UK
| | - Geraldine M Jowett
- Centre for Host-Microbiome Interactions, King's College London, London, T, UK
- Centre for Craniofacial and Regenerative Biology, King's College London, London, UK
- Centre for Stem Cells & Regenerative Medicine, King's College London, London, UK
| | - Emily Read
- Centre for Host-Microbiome Interactions, King's College London, London, T, UK
| | - Matthew Madgwick
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK
- Earlham Institute, Norwich Research Park, Norwich, UK
- Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
| | - Joana F Neves
- Centre for Host-Microbiome Interactions, King's College London, London, T, UK
| | - Tamas Korcsmaros
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK
- Earlham Institute, Norwich Research Park, Norwich, UK
- Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
| | - Richard G Jenner
- UCL Cancer Institute and CRUK City of London Centre, University College London, London, UK
| | - Lucy S K Walker
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection and Immunity, Royal Free Campus, London, UK
| | - Nick Powell
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK.
| | - Graham M Lord
- School of Immunology and Microbial Sciences, King's College London, London, UK.
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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27
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King HAD, Lewin SR. Immune checkpoint inhibitors in infectious disease. Immunol Rev 2024; 328:350-371. [PMID: 39248154 PMCID: PMC11659942 DOI: 10.1111/imr.13388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/10/2024]
Abstract
Following success in cancer immunotherapy, immune checkpoint blockade is emerging as an exciting potential treatment for some infectious diseases, specifically two chronic viral infections, HIV and hepatitis B. Here, we will discuss the function of immune checkpoints, their role in infectious disease pathology, and the ability of immune checkpoint blockade to reinvigorate the immune response. We focus on blockade of programmed cell death 1 (PD-1) to induce durable immune-mediated control of HIV, given that anti-PD-1 can restore function to exhausted HIV-specific T cells and also reverse HIV latency, a long-lived form of viral infection. We highlight several key studies and future directions of research in relation to anti-PD-1 and HIV persistence from our group, including the impact of immune checkpoint blockade on the establishment (AIDS, 2018, 32, 1491), maintenance (PLoS Pathog, 2016, 12, e1005761; J Infect Dis, 2017, 215, 911; Cell Rep Med, 2022, 3, 100766) and reversal of HIV latency (Nat Commun, 2019, 10, 814; J Immunol, 2020, 204, 1242), enhancement of HIV-specific T cell function (J Immunol, 2022, 208, 54; iScience, 2023, 26, 108165), and investigating the effects of anti-PD-1 and anti-CTLA-4 in vivo in people with HIV on ART with cancer (Sci Transl Med, 2022, 14, eabl3836; AIDS, 2021, 35, 1631; Clin Infect Dis, 2021, 73, e1973). Our future work will focus on the impact of anti-PD-1 in vivo in people with HIV on ART without cancer and potential combinations of anti-PD-1 with other interventions, including therapeutic vaccines or antibodies and less toxic immune checkpoint blockers.
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Affiliation(s)
- Hannah A. D. King
- Department of Infectious DiseasesThe University of Melbourne at The Peter Doherty Institute for Infection and ImmunityMelbourneVictoriaAustralia
| | - Sharon R. Lewin
- Department of Infectious DiseasesThe University of Melbourne at The Peter Doherty Institute for Infection and ImmunityMelbourneVictoriaAustralia
- Victorian Infectious Diseases ServiceRoyal Melbourne Hospital at The Peter Doherty Institute for Infection and ImmunityMelbourneVictoriaAustralia
- Department of Infectious DiseasesAlfred Hospital and Monash UniversityMelbourneVictoriaAustralia
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28
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Martineau R, Susini S, Marabelle A. Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology. Immunol Rev 2024; 328:334-349. [PMID: 39663733 PMCID: PMC11659940 DOI: 10.1111/imr.13427] [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: 09/16/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 12/13/2024]
Abstract
Antagonistic monoclonal antibodies (mAbs) targeting inhibitory immune checkpoints have revolutionized the field of oncology. CTLA-4, PD-1, and LAG3 are three co-inhibitory receptors, which can be expressed by subsets of T cells and which play a role in the regulation of adaptive immune responses. Blocking these immune checkpoints receptors (or their ligands) with antagonistic antibodies can lead to tumor regressions and lasting remissions in some patients with cancer. Two anti-CTLA4, six anti-PD1, three anti-PD-L1, and one anti-LAG3 antibodies are currently approved by the FDA and EMA. Their mechanism of action, safety, and efficacy are linked to their affinity with Fc gamma receptors (FcγR) (so called "effector functions"). The anti-CTLA-4 antibodies ipilimumab (IgG1) and tremilimumab (IgG2a), and the anti-PD-L1 avelumab (IgG1) have isotypes with high affinity for activating FcγR and thereby can induce ADCC/ADCP. The effector function is required for the in vivo efficacy of anti-CTLA4 antibodies. For anti-PD(L)1 antibodies, where a pure antagonistic function ("checkpoint blockade") is sufficient, some mAbs are IgG1 but have been mutated in their Fc sequence (e.g., durvalumab and atezolizumab) or are IgG4 (e.g., nivolumab and pembrolizumab) to have low affinity for FcγR. Here, we review the impact of FcγR effector function on immune checkpoint blockers safety and efficacy in oncology.
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Affiliation(s)
- Romane Martineau
- Université Paris SaclayLe Kremlin‐BicetreFrance
- Centre d'Investigation Clinique BIOTHERIS, CIC 1428Institut National de la Santé et de la Recherche Médicale (INSERM)VillejuifFrance
| | - Sandrine Susini
- Centre d'Investigation Clinique BIOTHERIS, CIC 1428Institut National de la Santé et de la Recherche Médicale (INSERM)VillejuifFrance
- Translational Immunotherapy Research LaboratoryGustave RoussyVillejuifFrance
| | - Aurelien Marabelle
- Université Paris SaclayLe Kremlin‐BicetreFrance
- Centre d'Investigation Clinique BIOTHERIS, CIC 1428Institut National de la Santé et de la Recherche Médicale (INSERM)VillejuifFrance
- Translational Immunotherapy Research LaboratoryGustave RoussyVillejuifFrance
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29
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Foyle KL, Chin PY, Merkwirth C, Wilson J, Hosking SL, Green ES, Chong MY, Zhang B, Moldenhauer LM, Ferguson GD, Morris GP, Karras JG, Care AS, Robertson SA. IL-2 Complexed With Anti-IL-2 Antibody Expands the Maternal T-Regulatory Cell Pool and Alleviates Fetal Loss in Abortion-Prone Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:2128-2149. [PMID: 39117109 DOI: 10.1016/j.ajpath.2024.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 07/04/2024] [Accepted: 07/16/2024] [Indexed: 08/10/2024]
Abstract
Regulatory T (Treg) cells are essential for immune tolerance of embryo implantation, and insufficient Treg cells provokes early pregnancy loss. An abortion-prone mouse model was used to evaluate IL-2 complexed with JES6-1 anti-IL-2 antibody (IL-2/JES6-1) to boost uterine Treg cells and improve reproductive success. IL-2/JES6-1, but not IL-2/IgG, administered in periconception to CBA/J females mated with DBA/2 males elicited a greater than twofold increase in the proportion of CD4+ T cells expressing forkhead box P3 (FOXP3), and an increased ratio of FOXP3+ Treg cells/FOXP3- T conventional cells in the uterus and its draining lymph nodes at embryo implantation that was sustained into midgestation. An attenuated phenotype was evident in both thymic-derived and peripheral Treg cells with elevated cytotoxic T-lymphocyte antigen-4, CD25, and FOXP3 indicating improved suppressive function, as well as increased proliferative marker Ki-67. IL-2/JES6-1 treatment reduced fetal loss from 31% to 10%, accompanied by a 6% reduction in late gestation fetal weight, despite comparable placental size and architecture. Similar effects of IL-2/JES6-1 on Treg cells and fetal growth were seen in CBA/J females with healthy pregnancies sired by BALB/c males. These findings show that expanding the uterine Treg cell pool through targeting IL-2 signaling is a strategy worthy of further investigation for mitigating risk of immune-mediated fetal loss.
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Affiliation(s)
- Kerrie L Foyle
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Peck Y Chin
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | | | - Jasmine Wilson
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Shanna L Hosking
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Ella S Green
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Mei Y Chong
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Bihong Zhang
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Lachlan M Moldenhauer
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | | | - Gerald P Morris
- Department of Pathology, University of California, San Diego, La Jolla, California
| | | | - Alison S Care
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Sarah A Robertson
- The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia.
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30
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Lara-Vega I. Upgrading Melanoma Treatment: Promising Immunotherapies Combinations
in the Preclinical Mouse Model. CURRENT CANCER THERAPY REVIEWS 2024; 20:489-509. [DOI: 10.2174/0115733947263244231002042219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/27/2023] [Accepted: 08/25/2023] [Indexed: 01/03/2025]
Abstract
Background:
Melanoma, known for its high metastatic potential, does not respond well to
existing treatments in advanced stages. As a solution, immunotherapy-based treatments, including
anti-PD-1/L1 and anti-CTLA-4, have been developed and evaluated in preclinical mouse models to
overcome resistance. Although these treatments display the potential to suppress tumor growth, there
remains a crucial requirement for a thorough assessment of long-term efficacy in preventing metastasis
or recurrence and improving survival rates.
Methods:
From 2016 onwards, a thorough examination of combined immunotherapies for the treatment
of cutaneous melanoma in preclinical mouse models was conducted. The search was conducted
using MeSH Terms algorithms in PubMed®, resulting in the identification of forty-five studies that
met the rigorous inclusion criteria for screening.
Results:
The C57 mouse model bearing B16-melanoma has been widely utilized to assess the efficacy
of immunotherapies. The combination of therapies has demonstrated a synergistic impact, leading
to potent antitumor activity. One extensively studied method for establishing metastatic models involves
the intravenous administration of malignant cells, with several combined therapies under investigation.
The primary focus of evaluation has been on combined immunotherapies utilizing PD-
1/L1 and CTLA-4 blockade, although alternative immunotherapies not involving PD-1/L1 and
CTLA-4 blockade have also been identified. Additionally, the review provides detailed treatment regimens
for each combined approach.
Conclusion:
The identification of techniques for generating simulated models of metastatic melanoma
and investigating various therapeutic combinations will greatly aid in evaluating the overall systemic
efficacy of immunotherapy. This will be especially valuable for conducting short-term preclinical
experiments that have the potential for clinical studies.
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Affiliation(s)
- Israel Lara-Vega
- National School of Biological Sciences, IPN. Av. Wilfrido Massieu s/n, Professional Unit Adolfo Lopez Mateos, Mexico
City, CP 07738, Mexico
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31
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Wenzek C, Siemes D, Hönes GS, Pastille E, Härting N, Kaiser F, Moeller LC, Engel DR, Westendorf AM, Führer D. Lack of canonical thyroid hormone receptor α signaling changes regulatory T cell phenotype in female mice. iScience 2024; 27:110547. [PMID: 39175769 PMCID: PMC11340620 DOI: 10.1016/j.isci.2024.110547] [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: 03/25/2024] [Revised: 06/17/2024] [Accepted: 07/16/2024] [Indexed: 08/24/2024] Open
Abstract
The immune system has emerged as an important target of thyroid hormones (THs); however, the role of TH in T cells has so far remained elusive. In this study, we assessed the effect of TH receptor α (TRα) signaling on activation and function of T cells. Our findings show that lack of canonical TRα action not only increased the frequency of regulatory T cells (Treg) but propelled an activated and migratory Treg phenotype and nuclear factor κB (NF-κB) activation in Treg. Conversely, canonical TRα action reduced activation of the NF-κB pathway previously shown to play a pivotal role in Treg differentiation and function. Taken together, our findings demonstrate that TRα impacts T cell differentiation and phenotype. Given the well-known interaction of inflammation, immune responses, and TH axis in e.g., severe illness, altered TH-TRα signaling may have an important role in regulating T cell responses during disease.
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Affiliation(s)
- Christina Wenzek
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Devon Siemes
- Institute for Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - G. Sebastian Hönes
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Eva Pastille
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Nina Härting
- Institute for Human Genetics, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Frank Kaiser
- Institute for Human Genetics, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Lars C. Moeller
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Daniel R. Engel
- Institute for Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Astrid M. Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Dagmar Führer
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
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32
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Liao HX, Mao X, Wang L, Wang N, Ocansey DKW, Wang B, Mao F. The role of mesenchymal stem cells in attenuating inflammatory bowel disease through ubiquitination. Front Immunol 2024; 15:1423069. [PMID: 39185411 PMCID: PMC11341407 DOI: 10.3389/fimmu.2024.1423069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 07/22/2024] [Indexed: 08/27/2024] Open
Abstract
Inflammatory bowel disease (IBD), a condition of the digestive tract and one of the autoimmune diseases, is becoming a disease of significant global public health concern and substantial clinical burden. Various signaling pathways have been documented to modulate IBD, but the exact activation and regulatory mechanisms have not been fully clarified; thus, a need for constant exploration of the molecules and pathways that play key roles in the development of IBD. In recent years, several protein post-translational modification pathways, such as ubiquitination, phosphorylation, methylation, acetylation, and glycolysis, have been implicated in IBD. An aberrant ubiquitination in IBD is often associated with dysregulated immune responses and inflammation. Mesenchymal stem cells (MSCs) play a crucial role in regulating ubiquitination modifications through the ubiquitin-proteasome system, a cellular machinery responsible for protein degradation. Specifically, MSCs have been shown to influence the ubiquitination of key signaling molecules involved in inflammatory pathways. This paper reviews the recent research progress in MSC-regulated ubiquitination in IBD, highlighting their therapeutic potential in treating IBD and offering a promising avenue for developing targeted interventions to modulate the immune system and alleviate inflammatory conditions.
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Affiliation(s)
- Hong Xi Liao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang, Jiangsu, China
| | - Xiaojun Mao
- The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu, China
| | - Lan Wang
- Department of Laboratory Medicine, Danyang Blood Station, Zhenjiang, Jiangsu, China
| | - Naijian Wang
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang, Jiangsu, China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Bo Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang, Jiangsu, China
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Joo JS, Lee D, Hong JY. Multi-Layered Mechanisms of Immunological Tolerance at the Maternal-Fetal Interface. Immune Netw 2024; 24:e30. [PMID: 39246621 PMCID: PMC11377946 DOI: 10.4110/in.2024.24.e30] [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: 04/12/2024] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 09/10/2024] Open
Abstract
Pregnancy represents an immunological paradox where the maternal immune system must tolerate the semi-allogeneic fetus expressing paternally-derived Ags. Accumulating evidence over decades has revealed that successful pregnancy requires the active development of robust immune tolerance mechanisms. This review outlines the multi-layered processes that establish fetomaternal tolerance, including the physical barrier of the placenta, restricted chemokine-mediated leukocyte trafficking, lack of sufficient alloantigen presentation, the presence of immunosuppressive regulatory T cells and tolerogenic decidual natural killer cells, expression of immune checkpoint molecules, specific glycosylation patterns conferring immune evasion, and unique metabolic/hormonal modulations. Interestingly, many of the strategies that enable fetal tolerance parallel those employed by cancer cells to promote angiogenesis, invasion, and immune escape. As such, further elucidating the mechanistic underpinnings of fetal-maternal tolerance may reciprocally provide insights into developing novel cancer immunotherapies as well as understanding the pathogenesis of gestational complications linked to dysregulated tolerance processes.
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Affiliation(s)
- Jin Soo Joo
- Department of Systems Biology, Yonsei University, Seoul 03722, Korea
| | - Dongeun Lee
- Department of Systems Biology, Yonsei University, Seoul 03722, Korea
| | - Jun Young Hong
- Department of Systems Biology, Yonsei University, Seoul 03722, Korea
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34
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Younis A, Gribben J. Immune Checkpoint Inhibitors: Fundamental Mechanisms, Current Status and Future Directions. IMMUNO 2024; 4:186-210. [DOI: 10.3390/immuno4030013] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Immune checkpoint inhibitors (ICI) are a promising form of immunotherapy that have significantly changed the therapeutic landscape for many advanced cancers. They have shown unique clinical benefit against a broad range of tumour types and a strong overall impact on survival in studied patient populations. However, there are still many limitations holding back this immunotherapy from reaching its full potential as a possible curative option for advanced cancer patients. A great deal of research is being undertaken in the hope of driving advancements in this area, building a better understanding of the mechanisms behind immune checkpoint inhibition and ultimately developing more effective, safer, and wider-reaching agents. Taking into account the current literature on this topic, this review aims to explore in depth the basis of the use of ICIs in the treatment of advanced cancers, evaluate its efficacy and safety, consider its current limitations, and finally reflect on what the future holds for this very promising form of cancer immunotherapy.
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Affiliation(s)
- Abdullah Younis
- Barts and the London School of Medicine and Dentistry, London E1 2AD, UK
| | - John Gribben
- Barts Cancer Institute, Queen Mary University of London, London EC1M 6AU, UK
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35
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Xuan W, Wang S, Alarcon-Calderon A, Bagwell MS, Para R, Wang F, Zhang C, Tian X, Stalboerger P, Peterson T, Sabbah MS, Du Z, Sarrafian T, Mahlberg R, Hillestad ML, Rizzo SA, Paradise CR, Behfar A, Vassallo R. Nebulized platelet-derived extracellular vesicles attenuate chronic cigarette smoke-induced murine emphysema. Transl Res 2024; 269:76-93. [PMID: 38325750 DOI: 10.1016/j.trsl.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 01/31/2024] [Accepted: 02/04/2024] [Indexed: 02/09/2024]
Abstract
Chronic obstructive pulmonary disease (COPD) is a prevalent lung disease usually resulting from cigarette smoking (CS). Cigarette smoking induces oxidative stress, which causes inflammation and alveolar epithelial cell apoptosis and represents a compelling therapeutic target for COPD. Purified human platelet-derived exosome product (PEP) is endowed with antioxidant enzymes and immunomodulatory molecules that mediate tissue repair. In this study, a murine model of CS-induced emphysema was used to determine whether nebulized PEP can influence the development of CS-induced emphysema through the mitigation of oxidative stress and inflammation in the lung. Nebulization of PEP effectively delivered the PEP vesicles into the alveolar region, with evidence of their uptake by type I and type II alveolar epithelial cells and macrophages. Lung function testing and morphometric assessment showed a significant attenuation of CS-induced emphysema in mice treated with nebulized PEP thrice weekly for 4 weeks. Whole lung immuno-oncology RNA sequencing analysis revealed that PEP suppressed several CS-induced cell injuries and inflammatory pathways. Validation of inflammatory cytokines and apoptotic protein expression on the lung tissue revealed that mice treated with PEP had significantly lower levels of S100A8/A9 expressing macrophages, higher levels of CD4+/FOXP3+ Treg cells, and reduced NF-κB activation, inflammatory cytokine production, and apoptotic proteins expression. Further validation using in vitro cell culture showed that pretreatment of alveolar epithelial cells with PEP significantly attenuated CS extract-induced apoptotic cell death. These data show that nebulization of exosomes like PEP can effectively deliver exosome cargo into the lung, mitigate CS-induced emphysema in mice, and suppress oxidative lung injury, inflammation, and apoptotic alveolar epithelial cell death.
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Affiliation(s)
- Weixia Xuan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester 55905, Minnesota.; Department of Respiratory Medicine, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shaohua Wang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester 55905, Minnesota
| | - Amarilys Alarcon-Calderon
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester 55905, Minnesota
| | - Monique Simone Bagwell
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Rachel Para
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester 55905, Minnesota.; Touro College of Osteopathic Medicine, New York, NY
| | - Faping Wang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester 55905, Minnesota.; Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Chujie Zhang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester 55905, Minnesota.; Department of Cardiology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710000, China
| | - Xue Tian
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester 55905, Minnesota.; Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Paul Stalboerger
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Timothy Peterson
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Michael S Sabbah
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Zeji Du
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Tiffany Sarrafian
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Ryan Mahlberg
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Matthew L Hillestad
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Skylar A Rizzo
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Mayo Clinic Medical Scientist Training Program, Rochester, MN, USA
| | | | - Atta Behfar
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Center for Regenerative Therapeutics, Mayo Clinic, Rochester, MN, USA; Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA; Summer Undergraduate Research Fellowship, Mayo Clinic, Rochester, MN, USA; Marriott Heart Disease Research Program, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Robert Vassallo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester 55905, Minnesota.; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
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36
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Su QY, Li HC, Jiang XJ, Jiang ZQ, Zhang Y, Zhang HY, Zhang SX. Exploring the therapeutic potential of regulatory T cell in rheumatoid arthritis: Insights into subsets, markers, and signaling pathways. Biomed Pharmacother 2024; 174:116440. [PMID: 38518605 DOI: 10.1016/j.biopha.2024.116440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 03/24/2024] Open
Abstract
Rheumatoid arthritis (RA) is a complex autoimmune inflammatory rheumatic disease characterized by an imbalance between immunological reactivity and immune tolerance. Regulatory T cells (Tregs), which play a crucial role in controlling ongoing autoimmunity and maintaining peripheral tolerance, have shown great potential for the treatment of autoimmune inflammatory rheumatic diseases such as RA. This review aims to provide an updated summary of the latest insights into Treg-targeting techniques in RA. We focus on current therapeutic strategies for targeting Tregs based on discussing their subsets, surface markers, suppressive function, and signaling pathways in RA.
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Affiliation(s)
- Qin-Yi Su
- The Second Hospital of Shanxi Medical University, Department of Rheumatology, Taiyuan, China; Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Huan-Cheng Li
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Xiao-Jing Jiang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Zhong-Qing Jiang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Yan Zhang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - He-Yi Zhang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Sheng-Xiao Zhang
- The Second Hospital of Shanxi Medical University, Department of Rheumatology, Taiyuan, China; Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China.
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37
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Casagrande S, Sopetto GB, Bertalot G, Bortolotti R, Racanelli V, Caffo O, Giometto B, Berti A, Veccia A. Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations. Cancers (Basel) 2024; 16:1440. [PMID: 38611115 PMCID: PMC11011060 DOI: 10.3390/cancers16071440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.
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Affiliation(s)
- Silvia Casagrande
- Unit of Neurology, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari-APSS, 38122 Trento, Italy; (S.C.); (B.G.)
| | - Giulia Boscato Sopetto
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
| | - Giovanni Bertalot
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Multizonal Unit of Pathology, APSS, 38122 Trento, Italy
| | - Roberto Bortolotti
- Unit of Rheumatology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy;
| | - Vito Racanelli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Unit of Internal Medicine, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy
| | - Orazio Caffo
- Unit of Oncology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy; (O.C.); (A.V.)
| | - Bruno Giometto
- Unit of Neurology, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari-APSS, 38122 Trento, Italy; (S.C.); (B.G.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Department of Psychology and Cognitive Sciences (DIPSCO), University of Trento, 38122 Trento, Italy
| | - Alvise Berti
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Unit of Rheumatology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy;
| | - Antonello Veccia
- Unit of Oncology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy; (O.C.); (A.V.)
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38
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Sharma S, Singh N, Turk AA, Wan I, Guttikonda A, Dong JL, Zhang X, Opyrchal M. Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions. World J Gastroenterol 2024; 30:1815-1835. [PMID: 38659481 PMCID: PMC11036501 DOI: 10.3748/wjg.v30.i13.1815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
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Affiliation(s)
- Samantha Sharma
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Naresh Singh
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Anita Ahmed Turk
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Isabella Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Akshay Guttikonda
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Julia Lily Dong
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Mateusz Opyrchal
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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Pipitone RM, Lupo G, Zito R, Javed A, Petta S, Pennisi G, Grimaudo S. The PD-1/PD-L1 Axis in the Biology of MASLD. Int J Mol Sci 2024; 25:3671. [PMID: 38612483 PMCID: PMC11011676 DOI: 10.3390/ijms25073671] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/18/2024] [Accepted: 03/19/2024] [Indexed: 04/14/2024] Open
Abstract
Metabolic Dysfunction-Associated Steatotic Liver (MASL), previously named nonalcoholic fatty liver (NAFL), is a multifactorial disease in which metabolic, genetic, and environmental risk factors play a predominant role. Obesity and type 2 diabetes act as triggers of the inflammatory response, which contributes to the progression of MASL to Metabolic Dysfunction-Associated Steatohepatitis and the development of hepatocellular carcinoma. In the liver, several parenchymal, nonparenchymal, and immune cells maintain immunological homeostasis, and different regulatory pathways balance the activation of the innate and adaptative immune system. PD-1/PD-L1 signaling acts, in the maintenance of the balance between the immune responses and the tissue immune homeostasis, promoting self-tolerance through the modulation of activated T cells. Recently, PD-1 has received much attention for its roles in inducing an exhausted T cells phenotype, promoting the tumor escape from immune responses. Indeed, in MASLD, the excessive fat accumulation dysregulates the immune system, increasing cytotoxic lymphocytes and decreasing their cytolytic activity. In this context, T cells exacerbate liver damage and promote tumor progression. The aim of this review is to illustrate the main pathogenetic mechanisms by which the immune system promotes the progression of MASLD and the transition to HCC, as well as to discuss the possible therapeutic applications of PD-1/PD-L1 target therapy to activate T cells and reinvigorate immune surveillance against cancer.
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Qi H, Sun Z, Gao T, Yao Y, Wang Y, Li W, Wang X, Wang X, Liu D, Jiang JD. Genetic fusion of CCL11 to antigens enhances antigenicity in nucleic acid vaccines and eradicates tumor mass through optimizing T-cell response. Mol Cancer 2024; 23:46. [PMID: 38459592 PMCID: PMC10921619 DOI: 10.1186/s12943-024-01958-4] [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: 09/20/2023] [Accepted: 02/13/2024] [Indexed: 03/10/2024] Open
Abstract
Nucleic acid vaccines have shown promising potency and efficacy for cancer treatment with robust and specific T-cell responses. Improving the immunogenicity of delivered antigens helps to extend therapeutic efficacy and reduce dose-dependent toxicity. Here, we systematically evaluated chemokine-fused HPV16 E6/E7 antigen to improve the cellular and humoral immune responses induced by nucleotide vaccines in vivo. We found that fusion with different chemokines shifted the nature of the immune response against the antigens. Although a number of chemokines were able to amplify specific CD8 + T-cell or humoral response alone or simultaneously. CCL11 was identified as the most potent chemokine in improving immunogenicity, promoting specific CD8 + T-cell stemness and generating tumor rejection. Fusing CCL11 with E6/E7 antigen as a therapeutic DNA vaccine significantly improved treatment effectiveness and caused eradication of established large tumors in 92% tumor-bearing mice (n = 25). Fusion antigens with CCL11 expanded the TCR diversity of specific T cells and induced the infiltration of activated specific T cells, neutrophils, macrophages and dendritic cells (DCs) into the tumor, which created a comprehensive immune microenvironment lethal to tumor. Combination of the DNA vaccine with anti-CTLA4 treatment further enhanced the therapeutic effect. In addition, CCL11 could also be used for mRNA vaccine design. To summarize, CCL11 might be a potent T cell enhancer against cancer.
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Affiliation(s)
- Hailong Qi
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
- Newish Biological R&D Center, Wuxi, China.
| | - Zhongjie Sun
- State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
- Newish Biological R&D Center, Wuxi, China
| | - Tianle Gao
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | | | - Yu Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
- Newish Biological R&D Center, Wuxi, China
| | - Weiwei Li
- Newish Biological R&D Center, Wuxi, China
| | | | | | - Defang Liu
- Newish Biological R&D Center, Wuxi, China
| | - Jian-Dong Jiang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
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Singh V, Nandi S, Ghosh A, Adhikary S, Mukherjee S, Roy S, Das C. Epigenetic reprogramming of T cells: unlocking new avenues for cancer immunotherapy. Cancer Metastasis Rev 2024; 43:175-195. [PMID: 38233727 DOI: 10.1007/s10555-024-10167-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 01/02/2024] [Indexed: 01/19/2024]
Abstract
T cells, a key component of cancer immunotherapy, undergo a variety of histone modifications and DNA methylation changes since their bone marrow progenitor stages before developing into CD8+ and CD4+ T cells. These T cell types can be categorized into distinct subtypes based on their functionality and properties, such as cytotoxic T cells (Tc), helper T cells (Th), and regulatory T cells (Treg) as subtypes for CD8+ and CD4+ T cells. Among these, the CD4+ CD25+ Tregs potentially contribute to cancer development and progression by lowering T effector (Teff) cell activity under the influence of the tumor microenvironment (TME). This contributes to the development of therapeutic resistance in patients with cancer. Subsequently, these individuals become resistant to monoclonal antibody therapy as well as clinically established immunotherapies. In this review, we delineate the different epigenetic mechanisms in cancer immune response and its involvement in therapeutic resistance. Furthermore, the possibility of epi-immunotherapeutic methods based on histone deacetylase inhibitors and histone methyltransferase inhibitors are under investigation. In this review we highlight EZH2 as the principal driver of cancer cell immunoediting and an immune escape regulator. We have addressed in detail how understanding T cell epigenetic regulation might bring unique inventive strategies to overcome drug resistance and increase the efficacy of cancer immunotherapy.
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Affiliation(s)
- Vipin Singh
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Sandhik Nandi
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Aritra Ghosh
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
- Indian Institute of Science Education and Research, Kolkata, India
| | - Santanu Adhikary
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
- Structural Biology & Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata, 700032, India
| | - Shravanti Mukherjee
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
| | - Siddhartha Roy
- Structural Biology & Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata, 700032, India
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India.
- Homi Bhabha National Institute, Mumbai, 400094, India.
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James KD, Cosway EJ, Parnell SM, White AJ, Jenkinson WE, Anderson G. Assembling the thymus medulla: Development and function of epithelial cell heterogeneity. Bioessays 2024; 46:e2300165. [PMID: 38161233 PMCID: PMC11475500 DOI: 10.1002/bies.202300165] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 01/03/2024]
Abstract
The thymus is a unique primary lymphoid organ that supports the production of self-tolerant T-cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus-dependent T-cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T-cell clones, thereby counterbalancing the potential for random T-cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self-tolerant T-cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function.
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Affiliation(s)
- Kieran D. James
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | - Emilie J. Cosway
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | - Sonia M. Parnell
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | - Andrea J. White
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | | | - Graham Anderson
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
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Kong Y, Wang X, Qie R. Immunotherapy-associated cardiovascular toxicities: insights from preclinical and clinical studies. Front Oncol 2024; 14:1347140. [PMID: 38482205 PMCID: PMC10932998 DOI: 10.3389/fonc.2024.1347140] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/12/2024] [Indexed: 11/02/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have become a widely accepted and effective treatment for various types of solid tumors. Recent studies suggest that cardiovascular immune-related adverse events (irAEs) specifically have an incidence rate ranging from 1.14% to more than 5%. Myocarditis is the most common observed cardiovascular irAE. Others include arrhythmias, pericardial diseases, vasculitis, and a condition resembling takotsubo cardiomyopathy. Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway, and the recently discovered lymphocyte-activation gene 3 (LAG-3) pathway, play a critical role in boosting the body's natural immune response against cancer cells. While ICIs offer significant benefits in terms of augmenting immune function, they can also give rise to unwanted inflammatory side effects known as irAEs. The occurrence of irAEs can vary in severity, ranging from mild to severe, and can impact the overall clinical efficacy of these agents. This review aims to summarize the underlying mechanisms of cardiovascular irAE from both preclinical and clinical studies for a better understanding of cardiovascular irAE in clinical application.
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Affiliation(s)
- Youqian Kong
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xiaoyu Wang
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Rui Qie
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Shalitin S. Endocrine-Related Adverse Conditions in Pediatric Patients Treated with Immune Checkpoint Inhibition for Malignancies. Horm Res Paediatr 2024; 98:124-135. [PMID: 38402861 DOI: 10.1159/000537969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/06/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND In recent years, remarkable advances in cancer immunotherapy have been introduced in the field of oncology. Since the discovery of immune checkpoint inhibitors (ICIs), these groups of medications have become a crucial treatment for several types of adult cancer. SUMMARY To date, pediatric experience with this group of medications is limited. Nevertheless, as clinicians, we have to be aware of the possible immune-related adverse events including immune-related endocrinopathies (thyroid dysfunction, diabetes mellitus, adrenal insufficiency, and pituitary insufficiency) that have been reported regarding these medications. These adverse events probably result from uncontrolled activation of the immune system. KEY MESSAGE Early diagnosis, monitoring, and treatment of immune-related endocrinopathies associated with ICIs treatment are also essential for the best supportive care and administration of ICIs in pediatric patients. This review presents the current data on the immune-related endocrinopathies associated with the ICIs treatment, with suggestions for management.
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Affiliation(s)
- Shlomit Shalitin
- The Jesse Z. and Lea Shafer Institute of Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
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45
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Kennedy PT, Saulters EL, Duckworth AD, Lim YJ, Woolley JF, Slupsky JR, Cragg MS, Ward FJ, Dahal LN. Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity. Mol Ther 2024; 32:457-468. [PMID: 38053333 PMCID: PMC10861965 DOI: 10.1016/j.ymthe.2023.11.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/12/2023] [Accepted: 11/30/2023] [Indexed: 12/07/2023] Open
Abstract
CTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumor control. Antibodies targeting CTLA-4 have been promising treatments for numerous cancers, but the mechanistic basis of their anti-tumoral immune-boosting effects is poorly understood. Although the ctla4 gene also encodes an alternatively spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in a murine cancer model. We show that expression of sCTLA-4 by tumor cells suppresses CD8+ T cells in vitro and accelerates growth and experimental metastasis of murine tumors in vivo. These effects were accompanied by modification of the immune infiltrate, notably restraining CD8+ T cells in a non-cytotoxic state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoral CD8+ T cell activation and cytolytic potential, correlating with therapeutic efficacy and tumor control. This previously unappreciated role of sCTLA-4 suggests that the biology and function of multi-gene products of immune checkpoint receptors need to be fully elucidated for improved mechanistic understanding of cancer immunotherapies.
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Affiliation(s)
- Paul T Kennedy
- Department of Pharmacology and Therapeutics, University of Liverpool, L69 3GE Liverpool, UK
| | - Emma L Saulters
- Department of Pharmacology and Therapeutics, University of Liverpool, L69 3GE Liverpool, UK
| | - Andrew D Duckworth
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, L69 3GE Liverpool, UK
| | - Yeong Jer Lim
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, L69 3GE Liverpool, UK
| | - John F Woolley
- Department of Pharmacology and Therapeutics, University of Liverpool, L69 3GE Liverpool, UK
| | - Joseph R Slupsky
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, L69 3GE Liverpool, UK
| | - Mark S Cragg
- Centre for Cancer Immunology, University of Southampton, SO16 6YD Southampton, UK
| | - Frank J Ward
- Department of Immunology, University of Aberdeen, AB25 2ZD Aberdeen, UK
| | - Lekh N Dahal
- Department of Pharmacology and Therapeutics, University of Liverpool, L69 3GE Liverpool, UK.
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46
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Cui W, Liu S. Optimization of adaptation parameters from adhesion cell culture in serum-containing media to suspension in chemically defined media by superlative box design. Cytotechnology 2024; 76:39-52. [PMID: 38304631 PMCID: PMC10828141 DOI: 10.1007/s10616-023-00596-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 09/04/2023] [Indexed: 02/03/2024] Open
Abstract
A new design of experiments-superlative box design (SBD), was adopted to optimize the adaptation of Chinese hamster ovary cells from adhesion culture to serum-free suspension culture. It is a general trend to use a serum-free medium instead of a serum-containing medium. The advantage of serum-free medium (chemically defended) is that it does not contain unknown components and avoids safety issues. SBD requires fewer experiments while ensuring a sufficient number of experiments and uniformity in the distribution of experiments amongst all the factors. Six factors were considered in this experimental design with 43 runs plus three more repeating center runs. The cell line was adapted to serum-free media by gradually reducing serum, and from adherent to suspension by rotating at various speeds in a shake flask. Response surface methodology was applied to find the optimum condition. The optimized cell density reached 7.02 × 105 cells/mL, calculated by the quadratic model. Experiments validated the predicted cell adaptation with the maximum cell density. Three suspension runs were selected randomly to perform in the bioreactor to validate cell stability and production homogeneity. This study provides an efficient method to transfer adherent cells to suspension cells and is the first to successfully use SBD and establish a parameter quadratic optimization model.
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Affiliation(s)
- Wanyue Cui
- Department of Chemical Engineering, SUNY College of Environmental Science and Forestry, Syracuse, NY 13210 USA
| | - Shijie Liu
- Department of Chemical Engineering, SUNY College of Environmental Science and Forestry, Syracuse, NY 13210 USA
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47
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Liu Z, Baines KJ, Niessen NM, Heer MK, Clark D, Bishop GA, Trevillian PR. Characterizing Foxp3 + and Foxp3 - T cells in the homeostatic state and after allo-activation: resting CD4 +Foxp3 + Tregs have molecular characteristics of activated T cells. Front Immunol 2024; 15:1292158. [PMID: 38333213 PMCID: PMC10850883 DOI: 10.3389/fimmu.2024.1292158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/08/2024] [Indexed: 02/10/2024] Open
Abstract
Due to the intracellular expression of Foxp3 it is impossible to purify viable Foxp3+ cells on the basis of Foxp3 staining. Consequently CD4+Foxp3+ regulatory T cells (Tregs) in mice have mostly been characterized using CD4+CD25+ T cells or GFP-Foxp3 reporter T cells. However, these two populations cannot faithfully represent Tregs as the expression of CD25 and Foxp3 does not completely overlap and GFP+Foxp3+ reporter T cells have been reported to be functionally altered. The aim of this study was to characterize normal Tregs without separating Foxp3+ and Foxp3- cells for the expression of the main functional molecules and proliferation behaviors by flow cytometry and to examine their gene expression characteristics through differential gene expression. Our data showed that the expressions of Foxp3, CD25, CTLA-4 (both intracellular and cell surface) and PD-1 was mostly confined to CD4+ T cells and the expression of Foxp3 did not completely overlap with the expression of CD25, CTLA-4 or PD-1. Despite higher levels of expression of the T cell inhibitory molecules CTLA-4 and PD-1, Tregs maintained higher levels of Ki-67 expression in the homeostatic state and had greater proliferation in vivo after allo-activation than Tconv. Differential gene expression analysis revealed that resting Tregs exhibited immune activation markers characteristic of activated Tconv. This is consistent with the flow data that the T cell activation markers CD25, CTLA-4, PD-1, and Ki-67 were much more strongly expressed by Tregs than Tconv in the homeostatic state.
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Affiliation(s)
- Zilei Liu
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
- School of Medicine and Public Health, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - Katherine J. Baines
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
- School of Biomedical Sciences and Pharmacy, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - Natalie M. Niessen
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
| | - Munish K. Heer
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
| | - David Clark
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- School of Medicine and Public Health, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - G. Alexander Bishop
- Transplantation Immunobiology Group, University of Sydney Central Clinical School, Charles Perkins Centre, Faculty of Medicine and Health, Sydney, NSW, Australia
| | - Paul R. Trevillian
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
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Deng W, Zhao Z, Zou T, Kuang T, Wang J. Research Advances in Fusion Protein-Based Drugs for Diabetes Treatment. Diabetes Metab Syndr Obes 2024; 17:343-362. [PMID: 38288338 PMCID: PMC10823413 DOI: 10.2147/dmso.s421527] [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: 07/10/2023] [Accepted: 12/22/2023] [Indexed: 01/31/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood glucose levels, resulting in multi-organ dysfunction and various complications. Fusion proteins can form multifunctional complexes by combining the target proteins with partner proteins. It has significant advantages in improving the performance of the target proteins, extending their biological half-life, and enhancing patient drug compliance. Fusion protein-based drugs have emerged as promising new drugs in diabetes therapeutics. However, there has not been a systematic review of fusion protein-based drugs for diabetes therapeutics. Hence, we conducted a comprehensive review of published literature on diabetic fusion protein-based drugs for diabetes, with a primary focus on immunoglobulin G (IgG) fragment crystallizable (Fc) region, albumin, and transferrin (TF). This review aims to provide a reference for the subsequent development and clinical application of fusion protein-based drugs in diabetes therapeutics.
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Affiliation(s)
- Wenying Deng
- School of Basic Medical Sciences, University of South China, Hengyang, Hunan Province, 421001, People’s Republic of China
| | - Zeyi Zhao
- School of Basic Medical Sciences, University of South China, Hengyang, Hunan Province, 421001, People’s Republic of China
| | - Tao Zou
- Department of Cardiovascular Medicine, First Affiliated Hospital of University of South China, Hengyang, Hunan Province, 421001, People’s Republic of China
| | - Tongdong Kuang
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi Province, 541199, People’s Republic of China
| | - Jing Wang
- School of Basic Medical Sciences, University of South China, Hengyang, Hunan Province, 421001, People’s Republic of China
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Klaus T, Hieber C, Bros M, Grabbe S. Integrins in Health and Disease-Suitable Targets for Treatment? Cells 2024; 13:212. [PMID: 38334604 PMCID: PMC10854705 DOI: 10.3390/cells13030212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/13/2024] [Accepted: 01/22/2024] [Indexed: 02/10/2024] Open
Abstract
Integrin receptors are heterodimeric surface receptors that play multiple roles regarding cell-cell communication, signaling, and migration. The four members of the β2 integrin subfamily are composed of an alternative α (CD11a-d) subunit, which determines the specific receptor properties, and a constant β (CD18) subunit. This review aims to present insight into the multiple immunological roles of integrin receptors, with a focus on β2 integrins that are specifically expressed by leukocytes. The pathophysiological role of β2 integrins is confirmed by the drastic phenotype of patients suffering from leukocyte adhesion deficiencies, most often resulting in severe recurrent infections and, at the same time, a predisposition for autoimmune diseases. So far, studies on the role of β2 integrins in vivo employed mice with a constitutive knockout of all β2 integrins or either family member, respectively, which complicated the differentiation between the direct and indirect effects of β2 integrin deficiency for distinct cell types. The recent generation and characterization of transgenic mice with a cell-type-specific knockdown of β2 integrins by our group has enabled the dissection of cell-specific roles of β2 integrins. Further, integrin receptors have been recognized as target receptors for the treatment of inflammatory diseases as well as tumor therapy. However, whereas both agonistic and antagonistic agents yielded beneficial effects in animal models, the success of clinical trials was limited in most cases and was associated with unwanted side effects. This unfavorable outcome is most probably related to the systemic effects of the used compounds on all leukocytes, thereby emphasizing the need to develop formulations that target distinct types of leukocytes to modulate β2 integrin activity for therapeutic applications.
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Affiliation(s)
| | | | | | - Stephan Grabbe
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (T.K.); (C.H.); (M.B.)
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Hu Y, Dong Z, Liu K. Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery. J Exp Clin Cancer Res 2024; 43:23. [PMID: 38245798 PMCID: PMC10799433 DOI: 10.1186/s13046-024-02949-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/08/2024] [Indexed: 01/22/2024] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, tumor inflammation, metabolism reprogramming, drug resistance, cancer stemness. Therefore, STAT3 has become a promising therapeutic target in a wide range of cancers. This review focuses on the up-to-date knowledge of STAT3 signaling in cancer. We summarize both the positive and negative modulators of STAT3 together with the cancer hallmarks involving activities regulated by STAT3 and highlight its extremely sophisticated regulation on immunosuppression in tumor microenvironment and metabolic reprogramming. Direct and indirect inhibitors of STAT3 in preclinical and clinical studies also have been summarized and discussed. Additionally, we highlight and propose new strategies of targeting STAT3 and STAT3-based combinations with established chemotherapy, targeted therapy, immunotherapy and combination therapy. These efforts may provide new perspectives for STAT3-based target therapy in cancer.
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Affiliation(s)
- Yamei Hu
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
- Medical Research Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zigang Dong
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450008, Henan, China.
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China.
| | - Kangdong Liu
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450008, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, Henan, China.
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China.
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