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Lerch M, Ramanathan S. The pathogenesis of neurological immune-related adverse events following immune checkpoint inhibitor therapy. Semin Immunol 2025; 78:101956. [PMID: 40294474 DOI: 10.1016/j.smim.2025.101956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 04/01/2025] [Accepted: 04/03/2025] [Indexed: 04/30/2025]
Abstract
Cancer is a leading cause of morbidity and mortality worldwide. The development of immune checkpoint inhibitors (ICI) has revolutionised cancer therapy, and patients who were previously incurable can now have excellent responses. These therapies work by blocking inhibitory immune pathways, like cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene 3 (LAG-3); which leads to increased anti-tumour immune responses. However, their use can lead to the development of immune-related adverse events (irAEs), which may result in severe disability, interruption of cancer therapy, and even death. Neurological autoimmune sequelae occur in 1-10 % of patients treated with ICIs and can be fatal. They encompass a broad spectrum of diseases, may affect the central and the peripheral nervous system, and include syndromes like encephalitis, cerebellitis, neuropathy, and myositis. In some cases, neurological irAEs can be associated with autoantibodies recognising neuronal or glial targets. In this review, we first describe the key targets in ICI therapy, followed by a formulation of irAEs and their clinical presentations, where we focus on neurological syndromes. We comprehensively formulate the current literature evaluating cell surface and intracellular autoantibodies, cytokines, chemokines, leukocyte patterns, other blood derived biomarkers, and immunogenetic profiles; and highlight their impact on our understanding of the pathogenesis of neurological irAEs. Finally, we describe therapeutic pathways and patient outcomes, and provide an overview on future aspects of ICI cancer therapy.
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Affiliation(s)
- Magdalena Lerch
- Translational Neuroimmunology Group, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Sudarshini Ramanathan
- Translational Neuroimmunology Group, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Department of Neurology and Concord Clinical School, Concord Hospital, Sydney, Australia.
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2
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Ikeda H. Cancer immunotherapy in progress-an overview of the past 130 years. Int Immunol 2025; 37:253-260. [PMID: 39792088 PMCID: PMC11975553 DOI: 10.1093/intimm/dxaf002] [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: 05/07/2024] [Accepted: 01/09/2025] [Indexed: 01/12/2025] Open
Abstract
Since the first approval of an immune checkpoint inhibitor, we have witnessed the clinical success of cancer immunotherapy. Adoptive T-cell therapy with chimeric antigen receptor T (CAR-T) cells has shown remarkable efficacy in hematological malignancies. Concurrently with these successes, the cancer immunoediting concept that refined the cancer immunosurveillance concept underpinned the scientific mechanism and reason for past failures, as well as recent breakthroughs in cancer immunotherapy. Now, we face the next step of issues to be solved in this field, such as tumor heterogeneity, the tumor microenvironment, the metabolism of tumors and the immune system, and personalized approaches for patients, aiming to expand the population benefitted by the therapies.
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Affiliation(s)
- Hiroaki Ikeda
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan
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3
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Rezazadeh‐Gavgani E, Majidazar R, Lotfinejad P, Kazemi T, Shamekh A. Immune Checkpoint Molecules: A Review on Pathways and Immunotherapy Implications. Immun Inflamm Dis 2025; 13:e70196. [PMID: 40243372 PMCID: PMC12004596 DOI: 10.1002/iid3.70196] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 03/12/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Today, treating cancer patients with monoclonal antibodies (mAbs), by targeting immune checkpoints, is one of the most outstanding immunotherapeutic methods. Immune checkpoints are special molecules having regulatory role in immune system responses. Once these molecules are presented on cancer cells, these cells will be capable of evading the immune system through their own specific pathways. This Evasion can be prevented by counterbalancing immune system responses with immune checkpoints related antibodies. AIMS The current study aimed to highlight immunotherapy and its methods, describe the immune checkpoints pathways, outline the immune checkpoint inhibitors (ICIs), and recent advances in this field, and sketch an outlook on the best treatment options for the most prevalent cancers. MATERIALS & METHODS This research implemented a narrative review method. A comprehensive literature review on the history, molecular and cellular biology, and the clinical aspects of immune checkpoint molecules was performed to illustrate the pathways involved in various cancers. Also, currently-available and future potential immunotherapies targeting these pathways were extracted from the searched studies. RESULTS The immune checkpoint family consists of many molecules, including CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, and TIGIT. Attempts to modify these molecules in cancer treatment led to the development of therapeutic monoclonal antibodies. Most of these antibodies have entered clinical studies and some of them have been approved by the Food and Drug Administration (FDA) to be used in cancer patients' treatment plans. DISCUSSION With these novel treatments and the combination therapies they offer, there is also hope for better treatment outcomes for the previously untreatable metastatic cancers. In spite of the beneficial aspects of immune checkpoint therapy, similar to other treatments, they may cause side effects in some patients. Therefore, more studies are needed to reduce the probable side effects and uncover their underlying mechanism. CONCLUSION Based on the data shown in this review, there is still a lack of knowledge about the complete properties of ICIs and the possible combination therapies that we may be able to implement to achieve a better treatment response in cancer patients.
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Affiliation(s)
| | - Reza Majidazar
- Student Research CommitteeTabriz University of Medical SciencesTabrizIran
| | - Parisa Lotfinejad
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
- Department of ImmunologyTabriz University of Medical SciencesTabrizIran
| | - Tohid Kazemi
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
- Department of ImmunologyTabriz University of Medical SciencesTabrizIran
| | - Ali Shamekh
- Student Research CommitteeTabriz University of Medical SciencesTabrizIran
- Aging Research InstituteTabriz University of Medical SciencesTabrizIran
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Ward FJ, Kennedy PT, Al-Fatyan F, Dahal LN, Abu-Eid R. CTLA-4-two pathways to anti-tumour immunity? IMMUNOTHERAPY ADVANCES 2025; 5:ltaf008. [PMID: 40265076 PMCID: PMC12012449 DOI: 10.1093/immadv/ltaf008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 03/02/2025] [Indexed: 04/24/2025] Open
Abstract
Immune checkpoint inhibitor (ICI) therapies have revolutionized cancer therapy and improved patient outcomes in a range of cancers. ICIs enhance anti-tumour immunity by targeting the inhibitory checkpoint receptors CTLA-4, PD-1, PD-L1, and LAG-3. Despite their success, efficacy, and tolerance vary between patients, raising new challenges to improve these therapies. These could be addressed by the identification of robust biomarkers to predict patient outcome and a more complete understanding of how ICIs affect and are affected by the tumour microenvironment (TME). Despite being the first ICIs to be introduced, anti-CTLA-4 antibodies have underperformed compared with antibodies that target the PD-1/PDL-1 axis. This is due to the complexity regarding their precise mechanism of action, with two possible routes to efficacy identified. The first is a direct enhancement of effector T-cell responses through simple blockade of CTLA-4-'releasing the brakes', while the second requires prior elimination of regulatory T cells (TREG) to allow emergence of T-cell-mediated destruction of tumour cells. We examine evidence indicating both mechanisms exist but offer different antagonistic characteristics. Further, we investigate the potential of the soluble isoform of CTLA-4, sCTLA-4, as a confounding factor for current therapies, but also as a therapeutic for delivering antigen-specific anti-tumour immunity.
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Affiliation(s)
- Frank J Ward
- Medical Sciences and Nutrition, Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, United Kingdom
| | - Paul T Kennedy
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Farah Al-Fatyan
- Medical Sciences and Nutrition, Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, United Kingdom
| | - Lekh N Dahal
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Rasha Abu-Eid
- Medical Sciences and Nutrition, Institute of Dentistry, School of Medicine, Sciences & Nutrition, University of Aberdeen, Aberdeen, United Kingdom
- School of Dentistry, College of Medicine and Health, The University of Birmingham, Birmingham, United Kingdom
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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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Afshari AR, Sanati M, Ahmadi SS, Kesharwani P, Sahebkar A. Harnessing the capacity of phytochemicals to enhance immune checkpoint inhibitor therapy of cancers: A focus on brain malignancies. Cancer Lett 2024; 593:216955. [PMID: 38750720 DOI: 10.1016/j.canlet.2024.216955] [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: 04/05/2024] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/23/2024]
Abstract
Brain cancers, particularly glioblastoma multiforme (GBM), are challenging health issues with frequent unmet aspects. Today, discovering safe and effective therapeutic modalities for brain tumors is among the top research interests. Immunotherapy is an emerging area of investigation in cancer treatment. Since immune checkpoints play fundamental roles in repressing anti-cancer immunity, diverse immune checkpoint inhibitors (ICIs) have been developed, and some monoclonal antibodies have been approved clinically for particular cancers; nevertheless, there are significant concerns regarding their efficacy and safety in brain tumors. Among the various tools to modify the immune checkpoints, phytochemicals show good effectiveness and excellent safety, making them suitable candidates for developing better ICIs. Phytochemicals regulate multiple immunological checkpoint-related signaling pathways in cancer biology; however, their efficacy for clinical cancer immunotherapy remains to be established. Here, we discussed the involvement of immune checkpoints in cancer pathology and summarized recent advancements in applying phytochemicals in modulating immune checkpoints in brain tumors to highlight the state-of-the-art and give constructive prospects for future research.
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Affiliation(s)
- Amir R Afshari
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran; Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran; Experimental and Animal Study Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Seyed Sajad Ahmadi
- Department of Ophthalmology, Khatam-Ol-Anbia Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Kejamurthy P, Devi KTR. Immune checkpoint inhibitors and cancer immunotherapy by aptamers: an overview. Med Oncol 2023; 41:40. [PMID: 38158454 DOI: 10.1007/s12032-023-02267-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/22/2023] [Indexed: 01/03/2024]
Abstract
Efforts in cancer immunotherapy aim to counteract evasion mechanisms and stimulate the immune system to recognise and attack cancer cells effectively. Combination therapies that target multiple aspects of immune evasion are being investigated to enhance the overall efficacy of cancer immunotherapy. PD-1 (Programmed Cell Death Protein 1), CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), LAG-3 (Lymphocyte-Activation Gene 3), and TIM-3 (T Cell Immunoglobulin and Mucin Domain-Containing Protein3) are all immune checkpoint receptors that play crucial roles in regulating the immune response and maintaining self-tolerance often exploited by cancer cells to evade immune surveillance. Antibodies targeted against immune checkpoint inhibitors such as anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-CTLA-4 antibodies (e.g., Ipilimumab), and experimental drugs targeting LAG-3 and TIM-3, aim to block these interactions and unleash the immune system's ability to recognise and destroy cancer cells. The US FDA has approved different categories of immune checkpoint inhibitors that have been utilised successfully in some patients with metastatic melanoma, renal cell carcinoma, head and neck cancers, and non-small lung cancer. Although several immune checkpoint inhibitor antibodies have been developed, they exhibited immune-related adverse effects, resulting in hypophysitis, diabetes, and neurological issues. These adverse effects of antibodies can be reduced by developing aptamer against the target. Aptamers offer several advantages over traditional antibodies, such as improved specificity, reduced immunogenicity, and flexible design for reduced adverse effects that specifically target and block protein-protein or receptor-ligand interactions involved in immune checkpoint pathways. The current study aims to review the function of particular immune checkpoint inhibitors along with developed aptamer-mediated antitumor cytotoxicity in cancer treatment.
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Affiliation(s)
- Priyatharcini Kejamurthy
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - K T Ramya Devi
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
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Jenkins KA, Park M, Pederzoli-Ribeil M, Eskiocak U, Johnson P, Guzman W, McLaughlin M, Moore-Lai D, O'Toole C, Liu Z, Nicholson B, Flesch V, Qiu H, Clackson T, O'Hagan RC, Rodeck U, Karow M, O'Neil J, Williams JC. XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer. J Immunother Cancer 2023; 11:e007785. [PMID: 38164757 PMCID: PMC10729150 DOI: 10.1136/jitc-2023-007785] [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] [Accepted: 11/09/2023] [Indexed: 01/03/2024] Open
Abstract
INTRODUCTION The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb. METHODS XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region of XTX101 were included to enhance affinity for FcγRIII, which is expected to enhance potency through antibody-dependent cellular cytotoxicity. RESULTS Biophysical, biochemical, and cell-based assays demonstrate that the function of XTX101 depends on proteolytic activation. In human CTLA-4 transgenic mice, XTX101 monotherapy demonstrated significant tumor growth inhibition (TGI) including complete responses, increased intratumoral CD8+T cells, and regulatory T cell depletion within the TME while maintaining minimal pharmacodynamic effects in the periphery. XTX101 in combination with anti-PD-1 mAb treatment resulted in significant TGI and was well tolerated in mice. XTX101 was activated in primary human tumors across a range of tumor types including melanoma, renal cell carcinoma, colon cancer and lung cancer in an ex vivo assay system. CONCLUSIONS These data demonstrate that XTX101 retains the full potency of an Fc-enhanced CTLA-4 antagonist within the TME while minimizing the activity in non-tumor tissue, supporting the further evaluation of XTX101 in clinical studies.
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Affiliation(s)
- Kurt A Jenkins
- Xilio Therapeutics, Waltham, Massachusetts, USA
- Molecular Medicine, City of Hope National Medical Center, Beckman Research Institute, Duarte, California, USA
| | - Miso Park
- Molecular Medicine, City of Hope National Medical Center, Beckman Research Institute, Duarte, California, USA
| | | | | | - Parker Johnson
- Xilio Therapeutics, Waltham, Massachusetts, USA
- Molecular Medicine, City of Hope National Medical Center, Beckman Research Institute, Duarte, California, USA
| | | | | | | | | | - Zhen Liu
- Xilio Therapeutics, Waltham, Massachusetts, USA
| | | | - Veronica Flesch
- Molecular Medicine, City of Hope National Medical Center, Beckman Research Institute, Duarte, California, USA
| | - Huawei Qiu
- Xilio Therapeutics, Waltham, Massachusetts, USA
| | | | | | - Ulrich Rodeck
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | | | | | - John C Williams
- Molecular Medicine, City of Hope National Medical Center, Beckman Research Institute, Duarte, California, USA
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Roy D, Gilmour C, Patnaik S, Wang LL. Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors. Front Immunol 2023; 14:1264327. [PMID: 37928556 PMCID: PMC10620683 DOI: 10.3389/fimmu.2023.1264327] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/26/2023] [Indexed: 11/07/2023] Open
Abstract
The differentiation, survival, and effector function of tumor-specific CD8+ cytotoxic T cells lie at the center of antitumor immunity. Due to the lack of proper costimulation and the abundant immunosuppressive mechanisms, tumor-specific T cells show a lack of persistence and exhausted and dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, and LAG-3, contribute to dysfunctional CTLs and failed antitumor immunity. These coinhibitory receptors are collectively called immune checkpoint receptors (ICRs). Immune checkpoint inhibitors (ICIs) targeting these ICRs have become the cornerstone for cancer immunotherapy as they have established new clinical paradigms for an expanding range of previously untreatable cancers. Given the nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies are being tested to bring synergistic benefits to patients. In this review, we summarize the mechanisms of several emerging ICRs, including VISTA, TIGIT, TIM-3, and LAG-3, and the preclinical and clinical data supporting combinatorial strategies to improve existing ICI therapies.
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Affiliation(s)
- Dia Roy
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Cassandra Gilmour
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, United States
- Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Sachin Patnaik
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Li Lily Wang
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, United States
- Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States
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Chiorean AD, Vica ML, Bâlici Ș, Nicula GZ, Răcătăianu N, Bordea MA, Simon LM, Matei HV. The C55A Single Nucleotide Polymorphism in CTLA-4 Gene, a New Possible Biomarker in Thyroid Autoimmune Pathology Such as Hashimoto's Thyroiditis. Diagnostics (Basel) 2023; 13:2517. [PMID: 37568880 PMCID: PMC10417055 DOI: 10.3390/diagnostics13152517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Hashimoto's thyroiditis (HT) is a chronic autoimmune disorder characterized by the production of autoantibodies against the thyroid gland. Different studies have shown that several genes may be associated with HT, which explains why patients often have family members with thyroiditis or other autoimmune diseases. The aim of this case-control study was to evaluate the correlation between polymorphisms at the level of exon 1 from the CTLA-4 gene and the susceptibility to developing HT. In this study, we found that there is no statistically significant association between the polymorphism rs231775 (A22G in exon 1) of the CTLA-4 gene and a genetic predisposition to HT. In contrast, a strong association was discovered for the first time between C55A in exon 1 of the CTLA-4 gene and HT. Our findings suggest that there is a genetic relationship between the CTLA-4 (+55A/C) genotype and the seropositivity against thyroid autoantigens, such as anti-thyroid peroxidase (ATPO) and anti-thyroglobulin antibodies (ATG).
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Affiliation(s)
- Alin-Dan Chiorean
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
- Clinical Laboratory, Emergency Clinical Hospital for Children, 400370 Cluj-Napoca, Romania
| | - Mihaela Laura Vica
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
- Institute of Legal Medicine Cluj-Napoca, 400006 Cluj-Napoca, Romania
| | - Ștefana Bâlici
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
| | - Gheorghe Zsolt Nicula
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
| | - Nicoleta Răcătăianu
- Integrated Ambulatory of Endocrinology, Infectious Diseases Clinical Hospital, 400000 Cluj-Napoca, Romania;
| | - Mădălina Adriana Bordea
- Department of Microbiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.A.B.); (L.-M.S.)
| | - Laura-Mihaela Simon
- Department of Microbiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.A.B.); (L.-M.S.)
| | - Horea Vladi Matei
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (A.-D.C.); (Ș.B.); (G.Z.N.); (H.V.M.)
- Institute of Legal Medicine Cluj-Napoca, 400006 Cluj-Napoca, Romania
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Kashima S, Braun DA. The Changing Landscape of Immunotherapy for Advanced Renal Cancer. Urol Clin North Am 2023; 50:335-349. [PMID: 36948676 DOI: 10.1016/j.ucl.2023.01.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
The management of advanced renal cell carcinoma has advanced tremendously over the past decade, but most patients still do not receive durable clinical benefit from current therapies. Renal cellcarcinoma is an immunogenic tumor, historically with conventional cytokine therapies, such as interleukin-2 and interferon-α, and contemporarily with the introduction of immune checkpoint inhibitors. Now the central therapeutic strategy in renal cell carcinoma is combination therapies including immunecheckpoint inhibitors. In this Review, we look back on the historical changes in systemic therapy for advanced renal cell carcinoma, and focus on the latest developments and prospects in this field.
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Affiliation(s)
- Soki Kashima
- Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, 300 George Street, Suite 6400, New Haven, CT, USA; Department of Urology, Akita University, Graduate School of Medicine, Akita, Japan
| | - David A Braun
- Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, 300 George Street, Suite 6400, New Haven, CT, USA.
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12
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Bouqdayr M, Abbad A, Baba H, Saih A, Wakrim L, Kettani A. Computational analysis of structural and functional evaluation of the deleterious missense variants in the human CTLA4 gene. J Biomol Struct Dyn 2023; 41:14179-14196. [PMID: 36764830 DOI: 10.1080/07391102.2023.2178509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/04/2023] [Indexed: 02/12/2023]
Abstract
CTLA-4 is an immune checkpoint receptor that negatively regulates the T-cell function expressed after T-cell activation to break the immune response. The current study predicted the genomic analysis to explore the functional variations of missense SNPs in the human CTLA4 gene using PolyPhen2, SIFT, PANTHER, PROVEAN, Fathmm, Mutation Assessor, PhD-SNP, SNPs&GO, SNAP2, and MutPred2. Phylogenetic conservation protein was predicted by ConSurf. Protein structural analysis was carried out by I-Mutant3, MUpro, iStable2, PremPS, and ERIS servers. Molecular dynamics trajectory analysis (RMSD, RMSF, Rg, SASA, H-bonds, and PCA) was performed to analyze the dynamic behavior of native and mutant CTLA-4 at the atomic level. Our in-silico analysis suggested that C58S, G118R, P137Q, P137R, P137L, P138T, and G146L variants were predicted to be the most deleterious missense variants and highly conserved residues. Moreover, the molecular dynamics analysis proposed a decrease in the protein stability and compactness with the P137R and P138T highlighting the impact of these variants on the function of the CTLA-4 protein.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Meryem Bouqdayr
- Laboratory of Biology and Health, Faculty of Sciences Ben M'sick, Hassan II University of Casablanca, Casablanca, Morocco
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Anass Abbad
- Medical Virology and BSL-3 Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Hanâ Baba
- Laboratory of Biology and Health, Faculty of Sciences Ben M'sick, Hassan II University of Casablanca, Casablanca, Morocco
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Asmae Saih
- Laboratory of Biology and Health, Faculty of Sciences Ben M'sick, Hassan II University of Casablanca, Casablanca, Morocco
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Lahcen Wakrim
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Anass Kettani
- Laboratory of Biology and Health, Faculty of Sciences Ben M'sick, Hassan II University of Casablanca, Casablanca, Morocco
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13
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Chakraborty R, Darido C, Liu F, Maselko M, Ranganathan S. Head and Neck Cancer Immunotherapy: Molecular Biological Aspects of Preclinical and Clinical Research. Cancers (Basel) 2023; 15:cancers15030852. [PMID: 36765809 PMCID: PMC9913716 DOI: 10.3390/cancers15030852] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/23/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023] Open
Abstract
Breakthrough research in the field of immune checkpoint inhibitors and the development of a human papilloma virus vaccine triggered a plethora of research in the field of cancer immunotherapy. Both had significant effects on the treatment of head and neck squamous cell carcinoma. The advent of preclinical models and multidisciplinary approaches including bioinformatics, genetic engineering, clinical oncology, and immunology helped in the development of tumour-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy. Here, we discuss different immunotherapies such as adoptive T-cell transfer, immune checkpoint inhibitors, interleukins, and cancer vaccines for the treatment of head and neck cancer. This review showcases the intrinsic relation between the understanding and implementation of basic biology and clinical practice. We also address potential limitations of each immunotherapy approach and the advantages of personalized immunotherapy. Overall, the aim of this review is to encourage further research in the field of immunotherapy for head and neck cancer.
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Affiliation(s)
- Rajdeep Chakraborty
- Applied Biosciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW 2109, Australia
| | - Charbel Darido
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Fei Liu
- School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW 2109, Australia
| | - Maciej Maselko
- Applied Biosciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW 2109, Australia
| | - Shoba Ranganathan
- Applied Biosciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW 2109, Australia
- Correspondence:
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14
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Dong H, Li M, Yang C, Wei W, He X, Cheng G, Wang S. Combination therapy with oncolytic viruses and immune checkpoint inhibitors in head and neck squamous cell carcinomas: an approach of complementary advantages. Cancer Cell Int 2023; 23:1. [PMID: 36604694 PMCID: PMC9814316 DOI: 10.1186/s12935-022-02846-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023] Open
Abstract
Squamous cell carcinomas are the most common head and neck malignancies. Significant progress has been made in standard therapeutic methods combining surgery, radiation, and chemotherapy. Nevertheless, the 5-year survival rate remains at 40-50%. Immune checkpoint inhibitors (ICIs) are a new strategy for treating head and neck squamous cell carcinomas (HNSCCs). Still, the overall response and effective rates are poor, as HNSCCs are 'cold' tumors with an immunosuppressive tumor microenvironment (TME), limiting ICI's beneficial effects. In this case, transforming the tumor suppression microenvironment before using ICIs could be helpful. Oncolytic viruses (OVs) can transform cold tumors into hot tumors, improving the situation. Talimogene laherparepvec (T-VEC), oncolytic immunotherapy authorized for advanced melanoma, also showed good safety and antitumor activity in treating head and neck cancer and pancreatic cancer. In combination with pembrolizumab, T-Vec may have more anticancer efficacy than either drug alone. Therefore, understanding the mechanisms underpinning OVs and their potential synergism with ICIs could benefit patients with HNSCC.
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Affiliation(s)
- Hui Dong
- grid.252957.e0000 0001 1484 5512Department of Stomatology, Bengbu Medical College, 2600 Donghai Avenue, Bengbu, 233030 China ,grid.417401.70000 0004 1798 6507Department of Stomatology, Center for Plastic and Reconstructive Surgery, Cancer Center, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014 Zhejiang China
| | - Mengli Li
- grid.252957.e0000 0001 1484 5512Department of Stomatology, Bengbu Medical College, 2600 Donghai Avenue, Bengbu, 233030 China ,grid.417401.70000 0004 1798 6507Department of Stomatology, Center for Plastic and Reconstructive Surgery, Cancer Center, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014 Zhejiang China
| | - Chen Yang
- grid.417401.70000 0004 1798 6507Department of Ultrasound Medicine, Cancer Center, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014 Zhejiang China
| | - Wei Wei
- grid.506977.a0000 0004 1757 7957Postgraduate Training Base of Jinzhou Medical University (Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014 Zhejiang People’s Republic of China
| | - Xianglei He
- grid.417401.70000 0004 1798 6507Department of Pathology, Cancer Center, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014 Zhejiang China
| | - Gang Cheng
- grid.252957.e0000 0001 1484 5512Department of Stomatology, Bengbu Medical College, 2600 Donghai Avenue, Bengbu, 233030 China ,grid.417401.70000 0004 1798 6507Department of Stomatology, Center for Plastic and Reconstructive Surgery, Cancer Center, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014 Zhejiang China
| | - Shibing Wang
- grid.417401.70000 0004 1798 6507Cancer Center, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014 Zhejiang China
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15
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Iravani Saadi M, Jiang M, Banakar M, Mardani Valandani F, Ahmadyan M, Rostamipour HA, Kheradmand N, Noshadi N, Karimi Z, Nabi Abdolyousefi E, Ramzi M, Haghighinejad H, Yaghobi R, Hosseini F. Are the Costimulatory Molecule Gene Polymorphisms (CTLA-4) Associated With Infection in Organ Transplantation? A Meta-Analysis. Cell Transplant 2023; 32:9636897231151576. [PMID: 36840462 PMCID: PMC9969477 DOI: 10.1177/09636897231151576] [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: 07/03/2022] [Revised: 01/03/2023] [Accepted: 01/03/2023] [Indexed: 02/26/2023] Open
Abstract
Organ transplantation has been linked to certain gene polymorphisms. The effect of gene polymorphisms-associated organ transplantation gene on infection, on the other hand, is yet unknown. The research studying the link between the CTLA-4 rs5742909, rs733618, rs4553808, rs231775, and polymorphisms of the organ transplantation gene and infection were found in PubMed, Web of Science, Scopus, and Embase, and the published articles from 2012 to 2020 were gathered. For the best estimation of the intended results, a random-effects model was used in this meta-analysis. In this study, 1,567 studies were initially included and 9 eligible studies were eligible for further analyses. A significant correlation between CTLA4+49 [A/G-231775 odds ratio (OR) = 077, 0.59-0.95] and CTLA4 [rs5742909TT OR: 0.09, 0.27-0.45] gene polymorphism with infection in organ transplantation was observed. Also, no significant association was found between other CTLA4 gene polymorphisms with infection in organ transplantation. Further studies involving gene-gene and gene-diet interactions should be conducted to investigate this association with infection.
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Affiliation(s)
| | - Mingjun Jiang
- Graduate School of Jinzhou Medical
University, Jinzhou, Liaoning, China
| | - Morteza Banakar
- Dental Research Center, Dentistry
Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Ahmadyan
- Hematology Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
| | | | - Nadiya Kheradmand
- Hematology Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
| | - Nasrin Noshadi
- Hematology Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
| | - Zahed Karimi
- Hematology Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
- Hematology, Oncology and Bone Marrow
Transplantation Department, Shiraz University of Medical Sciences, Shiraz,
Iran
| | | | - Mani Ramzi
- Hematology Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
- Hematology, Oncology and Bone Marrow
Transplantation Department, Shiraz University of Medical Sciences, Shiraz,
Iran
| | | | - Ramin Yaghobi
- Transplant Research Center, Shiraz
University of Medical Sciences, Shiraz
| | - Fakhroddin Hosseini
- Hematology Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
- Hematology, Oncology and Bone Marrow
Transplantation Department, Shiraz University of Medical Sciences, Shiraz,
Iran
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16
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Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein-Protein Interaction between CTLA-4 and B7-1. Pharmaceuticals (Basel) 2022; 15:ph15121506. [PMID: 36558957 PMCID: PMC9784018 DOI: 10.3390/ph15121506] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/26/2022] [Accepted: 11/29/2022] [Indexed: 12/07/2022] Open
Abstract
Currently, various pharmaceutical modalities are being developed rapidly. Targeting protein-protein interactions (PPIs) is an important objective in such development. Cyclic peptides, because they have good specificity and activity, have been attracting much attention as an alternative to antibody drugs. However, cyclic peptides involve some difficulties, such as oral availability and cell permeability. Therefore, while small-molecule drugs still present many benefits, the screening of functional small-molecule compounds targeting PPIs requires a great deal of time and effort, including structural analysis of targets and hits. In this study, we investigated a rational two-step strategy to design small-molecule compounds targeting PPIs. First, we obtained inhibitory cyclic peptides that bind to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) by ribosomal display using PUREfrex® (PUREfrex®RD) to get structure-activity relation (SAR) information. Based on that information, we converted cyclic peptides to small molecules using PepMetics® scaffolds that can mimic the α-helix or β-turn of the peptide. Finally, we succeeded in generating small-molecule compounds with good IC50 (single-digit μM values) against CTLA-4. This strategy is expected to be a useful approach for small-molecule design targeting PPIs, even without having structural information such as that associated with X-ray crystal structures.
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17
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Sadeghi M, Khodakarami A, Ahmadi A, Fathi M, Gholizadeh Navashenaq J, Mohammadi H, Yousefi M, Hojjat-Farsangi M, Movasaghpour Akbari AA, Jadidi-Niaragh F. The prognostic and therapeutic potentials of CTLA-4 in hematological malignancies. Expert Opin Ther Targets 2022; 26:1057-1071. [PMID: 36683579 DOI: 10.1080/14728222.2022.2170781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
INTRODUCTION Hematological Malignancies (HMs) are a group of progressive, difficult-to-treat, and highly recurrent diseases. A suppressed phenotype of the immune system is present in HMs and growing evidence indicates the role of Cytotoxic T lymphocyte-Associated protein 4 (CTLA-4) in the course of HMs. AREAS COVERED This article reviews the recent literature on the role of CTLA-4 in different subtypes of HMs. Here, the studies on the expression pattern, its effect on the prognosis of different HMs, and polymorphisms of CTLA-4 have been elaborated. Finally, the effect of targeting CTLA-4 in vitro and in vivo, as well as in clinical trials, is discussed. EXPERT OPINION According to the recent literature, CTLA-4 is overexpressed in different HMs, which is correlated with poor survival, while it is associated with better a prognosis in Chronic Lymphocytic Leukemia (CLL). Targeting CTLA-4 in Acute Myeloid Leukemia (AML), Sezary Syndrome (SS), Hodgkin's Lymphoma (HL), and so on, is helpful. While this is not recommended and may even be harmful in multiple myeloma (MM) and CLL. Also, it seems that certain CTLA-4 gene polymorphisms are efficient factors in the course of HMs. Future studies may broaden our knowledge regarding the role of CTLA-4 in HMs.
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Affiliation(s)
- Mohammad Sadeghi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Atefeh Khodakarami
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Armin Ahmadi
- Department of Chemical and Materials Engineering, the University of Alabama in Huntsville, Huntsville, Alabama, USA
| | - Mehrdad Fathi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hamed Mohammadi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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18
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Asemani Y, Najafi S, Ezzatifar F, Zolbanin NM, Jafari R. Recent highlights in the immunomodulatory aspects of Treg cell-derived extracellular vesicles: special emphasis on autoimmune diseases and transplantation. Cell Biosci 2022; 12:67. [PMID: 35606869 PMCID: PMC9125934 DOI: 10.1186/s13578-022-00808-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 05/07/2022] [Indexed: 12/19/2022] Open
Abstract
In order to maintain immunological tolerance to self and non-self antigens, one’s T regulatory (Treg) cells play a critical role in the regulation of detrimental inflammation. Treg cells inhibit the immune system in a variety of ways, some of which are contact-dependent and the others are soluble factors. Extracellular vesicles (EVs) are mainly secretory membrane structures that play a pivotal role in intercellular communication in both the local and systemic environments, enabling the transport of proteins, lipids, and nucleic acids between immune and non-immune cells. A number of studies have shown that Treg-derived EVs are specially formulated intercellular exchanging devices capable of regulating immunological responses by producing a cell-free tolerogenic milieu. Some of the processes suggested include miRNA-induced gene shutdown and upmodulation, surface protein activity, and enzyme transfer. Instead of being influenced by external circumstances like Tregs, exosomes’ cohesive structure allows them to transmit their charge intact across the blood–brain barrier and deliver it to the target cell with particular receptors. These properties have resulted in the use of Treg-derived EVs' immunomodulatory effects moving beyond laboratory research and into preclinical applications in animal models of a variety of inflammatory, autoimmune, and transplant rejection disorders. However, insufficient evidence has been produced to permit enrollment in human clinical studies. As such, we begin our research by introducing the most potent immunosuppressive elements discovered in Treg-derived EVs elucidating likely mechanisms of action in inhibiting immunological responses. Following that, we address recent research on the potential of suppressive EVs to regulate autoimmune inflammatory responses and improve tissue transplant survival.
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19
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Irfan M, Iqbal T, Hashmi S, Ghani U, Bhatti A. Insilico prediction and functional analysis of nonsynonymous SNPs in human CTLA4 gene. Sci Rep 2022; 12:20441. [PMID: 36443461 PMCID: PMC9705290 DOI: 10.1038/s41598-022-24699-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022] Open
Abstract
The CTLA4 receptor is an immune checkpoint involved in the downregulation of T cells. Polymorphisms in this gene have been found to be associated with different diseases like rheumatoid arthritis, autosomal dominant immune dysregulation syndrome, juvenile idiopathic arthritis and autoimmune Addison's disease. Therefore, the identification of polymorphisms that have an effect on the structure and function of CTLA4 gene is important. Here we identified the most damaging missense or non-synonymous SNPs (nsSNPs) that might be crucial for the structure and function of CTLA4 using different bioinformatics tools. These in silico tools included SIFT, PROVEAN, PhD-SNP, PolyPhen-2 followed by MutPred2, I-Mutant 2.0 and ConSurf. The protein structures were predicted using Phyre2 and I-TASSER, while the gene-gene interactions were predicted by GeneMANIA and STRING. Our study identified three damaging missense SNPs rs1553657429, rs1559591863 and rs778534474 in coding region of CTLA4 gene. Among these SNPs the rs1553657429 showed a loss of potential phosphorylation site and was found to be highly conserved. The prediction of gene-gene interaction showed the interaction of CTlA4 with other genes and its importance in different pathways. This investigation of damaging nsSNPs can be considered in future while studying CTLA4 related diseases and can be of great importance in precision medicine.
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Affiliation(s)
- Muhammad Irfan
- grid.412117.00000 0001 2234 2376Healthcare Biotechnology, National University of Science and Technology, Islamabad H-12, 44000 Pakistan
| | - Talha Iqbal
- grid.412117.00000 0001 2234 2376Healthcare Biotechnology, National University of Science and Technology, Islamabad H-12, 44000 Pakistan
| | - Sakina Hashmi
- grid.412117.00000 0001 2234 2376Healthcare Biotechnology, National University of Science and Technology, Islamabad H-12, 44000 Pakistan
| | - Uzma Ghani
- grid.412117.00000 0001 2234 2376Healthcare Biotechnology, National University of Science and Technology, Islamabad H-12, 44000 Pakistan
| | - Attya Bhatti
- grid.412117.00000 0001 2234 2376Healthcare Biotechnology, National University of Science and Technology, Islamabad H-12, 44000 Pakistan
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20
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Biphenyl-based small molecule inhibitors: Novel cancer immunotherapeutic agents targeting PD-1/PD-L1 interaction. Bioorg Med Chem 2022; 73:117001. [PMID: 36126447 DOI: 10.1016/j.bmc.2022.117001] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/25/2022] [Accepted: 09/03/2022] [Indexed: 11/23/2022]
Abstract
The immune checkpoint proteins are those key to the body's immunity which can either boost the immune system to protect the body from pathogens; or suppress the body's immunity system for the goal of self-tolerance. Cancer cells have evolved some mechanisms to boost the immuno-inhibitory checkpoints to bypass the immune system of the body. The binding of Programmed Cell Death-1 (PD-1) protein with its ligand Programmed Cell Death Ligand-1 (PD-L1) promotes this kind of immune-inhibitory signal. The discovery of immune checkpoint inhibitors was started in the early 21st century; with some success through monoclonal antibodies, peptides, and small molecules. Being the most reliable and safest way to target immune checkpoints, the scientific community is exploring possibilities to develop small molecule inhibitors. Among the different scaffolds of the small molecule, the most exposed and researched core molecule is Biphenyl-based scaffolds. We have described all of the possible biphenyl-based small molecules in this article, as well as their interactions with various amino acids in the binding cavity. The link between the in silico, in vitro, and in vivo activities of the PD-1/PD-L1 inhibitors are well connected. The Tyr56, Met115, Ala121, and Asp122 were detected as the crucial amino acids of the PD-1/PD-L1 inhibition. Additionally, a detailed binding pocket analysis of the PD-L1 receptor was carried out, where it was observed and confirmed that the binding pocket is tunnel-shaped and hydrophobic in nature. Finally, the structure-activity relationship of the biphenyl-based small molecule inhibitors was developed based on their activity and the binding interactions.
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21
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Ghosh S, He X, Huang WC, Lovell JF. Immune checkpoint blockade enhances chemophototherapy in a syngeneic pancreatic tumor model. APL Bioeng 2022; 6:036105. [PMID: 36164594 PMCID: PMC9509203 DOI: 10.1063/5.0099811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/29/2022] [Indexed: 11/14/2022] Open
Abstract
Pancreatic cancer (PaCa) suffers from poor treatment options for locally advanced cases. Chemophototherapy (CPT) is an emerging anti-tumor modality, and porphyrin–phospholipid liposomes have been shown to be versatile drug carriers for CPT in preclinical rodent models. Here we show that in the syngeneic subcutaneous KPC PaCa tumor model, exhausted CD8+ T cells are localized in the tumor, and that CPT is enhanced in combination with immune checkpoint blockade (ICB). Addition of ICB using anti-programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies resulted in ablation of medium-sized, established KPC tumors (∼200 mm3) without recurrence for over 100 days. Mice rejected subsequent tumor re-challenge. Flow cytometry and tumor slice analysis following injection of a fluorescently labeled anti-PD-1 antibody showed that CPT improved antibody delivery to the tumor microenvironment. Treatment of large established tumors (∼400 mm3) using with CPT and ICB induced appreciable tumor regression and delay in regrowth. Taken together, these data demonstrate the utility of combining CPT with immunotherapies.
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Affiliation(s)
- Sanjana Ghosh
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA
| | - Xuedan He
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA
| | - Wei-Chiao Huang
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA
| | - Jonathan F Lovell
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA
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22
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Lashgari M, Keshavarz Shahbaz S, Javadi A, Sahmani M, Khalaji M, Maali A, Foroughi F. Survey of the association between polymorphisms of CTLA-4 exon 1 49 A/G genes with rheumatoid arthritis in Iran. J Immunoassay Immunochem 2022; 43:480-492. [PMID: 35607764 DOI: 10.1080/15321819.2022.2076109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which suppresses T cell proliferation, is a promising candidate for the susceptibility genes to rheumatic arthritis diseases (RA). This study aims to examine the association between the polymorphisms of the CTLA-4 exon 1(+ 49) genes with RA in the Qazvin city of Iran population. The polymerase chain reaction of genomic DNA-restriction fragment length polymorphism (PCR-RFLP) was applied to genotype the CTLA-4 exon 1(+ 49) polymorphisms in 105 RA patients and 90 control subjects. Laboratory diagnostic tests were also measured for RA and control groups. Our results did not demonstrate a significant difference in allele and genotype frequencies of the CTLA-4 exon 1(+ 49) between RA patients and the control group (p < .0001). There was no significant difference in age at onset, CRP, RF value in patients with RA according to the CTLA-4 polymorphisms; just anti-CCP showed a significant difference. Our data declared that polymorphisms of CTLA-4 exon 1(+ 49) genes are not correlated with RA susceptibility and its clinical and paraclinical manifestations.
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Affiliation(s)
- Mahin Lashgari
- Metabolic Disease Research Center, Research Institute for Prevention of non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amir Javadi
- Department of Community Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.,Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mehdi Sahmani
- Department of Biochemistry & Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Khalaji
- Department of Biochemistry & Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amirhosein Maali
- Department of Medical Biotechnology, School of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Farshad Foroughi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.,Department of Immunology, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
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23
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Liu J, Song G, Zhao G, Meng T. Gene polymorphism associated with FOXP3, CTLA-4 and susceptibility to pre-eclampsia: a meta-analysis and trial sequential analysis. J OBSTET GYNAECOL 2022; 42:1085-1091. [PMID: 35020557 DOI: 10.1080/01443615.2021.2002285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Previous studies have detected the correlation of polymorphisms in regulatory T cells associated genes FOXP3 and CTLA-4 with pre-eclampsia (PE) risk, but the results are inconsistent among studies. Eligible studies were retrieved in several database. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilised to evaluate the relationship between FOXP3 rs3761548, FOXP3 rs2232365, CTLA-4 rs231775 polymorphisms, and PE susceptibility in the genetic models. The subgroup analysis and trial sequential analysis were performed. Twelve studies with a total of 4658 participants were included. There was a statistically significant association between FOXP3 rs3761548 polymorphism and PE within the recessive model in Asian (OR = 0.54, 95% CI = 0.34-0.86). Trial sequential analysis indicated sufficient proof of such association in the Asian population. This meta-analysis provides sufficient statistical evidence indicating an association between FOXP3 rs3761548 polymorphism and PE risk in Asian.IMPACT STATEMENTWhat is already known on this subject? FOXP3 and CTLA4 are markers of regulatory T cells which play a crucial role during a preeclamptic pregnancy.What do the results of this study add? Eleven studies with a total of 4658 participants were included. There was a statistically significant association between FOXP3 rs3761548 polymorphism and pre-eclampsia (PE) within the recessive model in Asian (OR = 0.54, 95% CI = 0.34-0.86). Trial sequential analysis indicated sufficient proof of such association in the Asian population. However, there was no enough evidence could proof significant association between FOXP3 rs2232365 or CTLA-4 rs231775 polymorphism and PE.What are the implications of these findings for clinical practice and/or further research? This meta-analysis provides sufficient statistical evidence indicating an association between FOXP3 rs3761548 polymorphism and PE risk in Asian. The findings in this study may provide a basis for the further study on FOXP3 rs3761548 polymorphism in future research.
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Affiliation(s)
- Jing Liu
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Guang Song
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ge Zhao
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Tao Meng
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, China
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Kailashiya J, Kailashiya V, Singh U. CTLA4 gene polymorphism and its association with disease occurrence, clinical manifestations, serum markers and cytokine levels in SLE patients from North India. Indian J Dermatol 2022; 67:311. [DOI: 10.4103/ijd.ijd_82_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Current Immunotherapeutic Strategies Targeting the PD-1/PD-L1 Axis in Non-Small Cell Lung Cancer with Oncogenic Driver Mutations. Int J Mol Sci 2021; 23:ijms23010245. [PMID: 35008669 PMCID: PMC8745513 DOI: 10.3390/ijms23010245] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 12/26/2022] Open
Abstract
Treatment strategies targeting programed cell death 1 (PD-1) or its ligand, PD-L1, have been developed as immunotherapy against tumor progression for various cancer types including non-small cell lung cancer (NSCLC). The recent pivotal clinical trials of immune-checkpoint inhibiters (ICIs) combined with cytotoxic chemotherapy have reshaped therapeutic strategies and established various first-line standard treatments. The therapeutic effects of ICIs in these clinical trials were analyzed according to PD-L1 tumor proportion scores or tumor mutational burden; however, these indicators are insufficient to predict the clinical outcome. Consequently, molecular biological approaches, including multi-omics analyses, have addressed other mechanisms of cancer immune escape and have revealed an association of NSCLC containing specific driver mutations with distinct immune phenotypes. NSCLC has been characterized by driver mutation-defined molecular subsets and the effect of driver mutations on the regulatory mechanism of PD-L1 expression on the tumor itself. In this review, we summarize the results of recent clinical trials of ICIs in advanced NSCLC and the association between driver alterations and distinct immune phenotypes. We further discuss the current clinical issues with a future perspective for the role of precision medicine in NSCLC.
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Exploiting systems biology to investigate the gene modules and drugs in ovarian cancer: A hypothesis based on the weighted gene co-expression network analysis. Biomed Pharmacother 2021; 146:112537. [PMID: 34922114 DOI: 10.1016/j.biopha.2021.112537] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Ovarian cancer (OC) is one of the worrisome gynecological cancers worldwide. Given its considerable mortality rate, it is necessary to investigate its oncogenesis. METHODS In this study, we used systems biology approaches to describe the key gene modules, hub genes, and regulatory drugs associated with serous OC as the novel biomarkers using weighted gene co-expression network analysis (WGCNA). FINDINGS Our findings have demonstrated that the blue module genes (r = 0.8, p-value = 1e-16) are involved in OC progression. Based on gene enrichment analysis, the genes in this module are frequently involved in biological processes such as the Cyclic adenosine monophosphate (cAMP) signaling pathway and the cellular response to transforming growth factor-beta stimulation. The co-expression network has been built using the correlated module's top hub genes, which are ADORA1, ANO9, CD24P4, CLDN3, CLDN7, ELF3, KLHL14, PRSS8, RASAL1, RIPK4, SERINC2, and WNT7A. Finally, a drug-target network has been built to show the interaction of the FDA-approved drugs with hub genes. CONCLUSIONS Our results have discovered that ADORA1, ANO9, SERINC2, and KLHL14 are hub genes associated with serous OC. These genes can be considered as novel candidate target genes for treating OC.
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Bolandi N, Derakhshani A, Hemmat N, Baghbanzadeh A, Asadzadeh Z, Afrashteh Nour M, Brunetti O, Bernardini R, Silvestris N, Baradaran B. The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment. Int J Mol Sci 2021; 22:ijms221910719. [PMID: 34639059 PMCID: PMC8509619 DOI: 10.3390/ijms221910719] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/28/2021] [Accepted: 10/01/2021] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC.
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Affiliation(s)
- Nadia Bolandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Mina Afrashteh Nour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Oronzo Brunetti
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95100 Catania, Italy;
| | - Nicola Silvestris
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, 70124 Bari, Italy
- Correspondence: (N.S.); (B.B.); Tel.: +98-413-3371440 (B.B.); Fax: +98-413-3371311 (B.B.)
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 516615731, Iran
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran
- Correspondence: (N.S.); (B.B.); Tel.: +98-413-3371440 (B.B.); Fax: +98-413-3371311 (B.B.)
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Khan M, Arooj S, Wang H. Soluble B7-CD28 Family Inhibitory Immune Checkpoint Proteins and Anti-Cancer Immunotherapy. Front Immunol 2021; 12:651634. [PMID: 34531847 PMCID: PMC8438243 DOI: 10.3389/fimmu.2021.651634] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022] Open
Abstract
Co-inhibitory B7-CD28 family member proteins negatively regulate T cell responses and are extensively involved in tumor immune evasion. Blockade of classical CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) and PD-1 (programmed cell death protein-1) checkpoint pathways have become the cornerstone of anti-cancer immunotherapy. New inhibitory checkpoint proteins such as B7-H3, B7-H4, and BTLA (B and T lymphocyte attenuator) are being discovered and investigated for their potential in anti-cancer immunotherapy. In addition, soluble forms of these molecules also exist in sera of healthy individuals and elevated levels are found in chronic infections, autoimmune diseases, and cancers. Soluble forms are generated by proteolytic shedding or alternative splicing. Elevated circulating levels of these inhibitory soluble checkpoint molecules in cancer have been correlated with advance stage, metastatic status, and prognosis which underscore their broader involvement in immune regulation. In addition to their potential as biomarker, understanding their mechanism of production, biological activity, and pathological interactions may also pave the way for their clinical use as a therapeutic target. Here we review these aspects of soluble checkpoint molecules and elucidate on their potential for anti-cancer immunotherapy.
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Affiliation(s)
- Muhammad Khan
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Sumbal Arooj
- Department of Biochemistry, University of Sialkot, Sialkot, Pakistan
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
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Piotrowska M, Gliwiński M, Trzonkowski P, Iwaszkiewicz-Grzes D. Regulatory T Cells-Related Genes Are under DNA Methylation Influence. Int J Mol Sci 2021; 22:7144. [PMID: 34281195 PMCID: PMC8267835 DOI: 10.3390/ijms22137144] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
Regulatory T cells (Tregs) exert a highly suppressive function in the immune system. Disturbances in their function predispose an individual to autoimmune dysregulation, with a predominance of the pro-inflammatory environment. Besides Foxp3, which is a master regulator of these cells, other genes (e.g., Il2ra, Ctla4, Tnfrsf18, Ikzf2, and Ikzf4) are also involved in Tregs development and function. Multidimensional Tregs suppression is determined by factors that are believed to be crucial in the action of Tregs-related genes. Among them, epigenetic changes, such as DNA methylation, tend to be widely studied over the past few years. DNA methylation acts as a repressive mark, leading to diminished gene expression. Given the role of increased CpG methylation upon Tregs imprinting and functional stability, alterations in the methylation pattern can cause an imbalance in the immune response. Due to the fact that epigenetic changes can be reversible, so-called epigenetic modifiers are broadly used in order to improve Tregs performance. In this review, we place emphasis on the role of DNA methylation of the genes that are key regulators of Tregs function. We also discuss disease settings that have an impact on the methylation status of Tregs and systematize the usefulness of epigenetic drugs as factors able to influence Tregs functions.
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Affiliation(s)
| | | | | | - Dorota Iwaszkiewicz-Grzes
- Department of Medical Immunology, Medical University of Gdansk, 80-210 Gdańsk, Poland; (M.P.); (M.G.); (P.T.)
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30
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Goleva E, Lyubchenko T, Kraehenbuehl L, Lacouture ME, Leung DYM, Kern JA. Our current understanding of checkpoint inhibitor therapy in cancer immunotherapy. Ann Allergy Asthma Immunol 2021; 126:630-638. [PMID: 33716146 PMCID: PMC8713301 DOI: 10.1016/j.anai.2021.03.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/01/2021] [Accepted: 03/09/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Treatments with Food and Drug Administration-approved blocking antibodies targeting inhibitory cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) receptor, or programmed cell death ligand 1 (PD-L1), collectively named checkpoint inhibitors (CPIs), have been successful in producing long-lasting remissions, even in patients with advanced-stage cancers. However, these treatments are often accompanied by undesirable autoimmune and inflammatory side effects, sometimes bringing severe consequences for the patient. Rapid expansion of clinical applications necessitates a more nuanced understanding of CPI function in health and disease to develop new strategies for minimizing the negative side effects, while preserving the immunotherapeutic benefit. DATA SOURCES This review summarizes a new paradigm-shifting approach to cancer immunotherapy with the focus on the mechanism of action of immune checkpoints (CTLA4, PD-1, and its ligands). STUDY SELECTIONS We performed a literature search and identified relevant recent clinical reports, experimental research, and review articles. RESULTS This review highlights our understanding of the CPI mechanism of action on cellular and molecular levels. The authors also discuss how reactivation of T cell responses through the inhibition of CTLA4, PD-1, and PD-L1 is used for tumor inhibition in cancer immunotherapy. CONCLUSION Mechanisms of PD-1 and CTLA4 blockade and normal biological functions of these molecules are highly complex and require additional studies that will be critical for developing new approaches to dissociate the benefits of checkpoint blockade from off-target effects of the immune reactivation that leads to immune-related adverse events.
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Affiliation(s)
- Elena Goleva
- Department of Pediatrics, National Jewish Health, Denver, Colorado.
| | - Taras Lyubchenko
- Department of Pediatrics, National Jewish Health, Denver, Colorado
| | - Lukas Kraehenbuehl
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mario E Lacouture
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York
| | - Donald Y M Leung
- Department of Pediatrics, National Jewish Health, Denver, Colorado
| | - Jeffrey A Kern
- Division of Oncology, Department of Medicine, National Jewish Health, Denver, Colorado
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Almonte AA, Rangarajan H, Yip D, Fahrer AM. How does the gut microbiome influence immune checkpoint blockade therapy? Immunol Cell Biol 2021; 99:361-372. [PMID: 33147357 DOI: 10.1111/imcb.12423] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 08/21/2020] [Accepted: 11/01/2020] [Indexed: 01/11/2023]
Abstract
Immune checkpoint blockade (ICB) therapies are revolutionary cancer treatments; however, they only benefit about a third of patients. Therefore, extensive research is underway to find methods to improve their therapeutic efficacy. One avenue of study that has recently emerged is to consider the role the gut microbiome plays in therapeutic success. Several high-impact studies have repeatedly shown that the presence, composition and level of diversity of the gut flora directly impact cancer treatment outcome in both mice and patients. These studies have also highlighted the danger of using antibiotics shortly before or during cancer treatments. However, there are still several questions that need to be answered, including which bacteria promote the greatest benefit, the mechanisms by which they act and how we can use this information to influence treatment outcome. In this review, we explain how the gut microbiome was realized to be of such importance and propose hypotheses for why gut flora have such a critical impact on ICB therapeutic success. We also describe a hypothetical mechanism involving bacterial translocation out of the gut and into the tumor, whereby the bacteria act in an adjuvant capacity to facilitate an antitumor response. By highlighting key papers in the field, we hope to hasten research on the subject so as to find a means to improve the therapeutic efficacy of these ground-breaking cancer treatments.
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Affiliation(s)
- Andrew A Almonte
- Division of Biomedical Science and Biochemistry, Research School of Biology, Australian National University, Acton, ACT, Australia
| | - Hareesha Rangarajan
- Division of Biomedical Science and Biochemistry, Research School of Biology, Australian National University, Acton, ACT, Australia
| | - Desmond Yip
- Department of Medical Oncology, The Canberra Hospital and ANU Medical School, Australian National University, Garran, ACT, Australia
| | - Aude M Fahrer
- Division of Biomedical Science and Biochemistry, Research School of Biology, Australian National University, Acton, ACT, Australia
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Kolb HR, Borcherding N, Zhang W. Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:229-256. [PMID: 33523451 DOI: 10.1007/978-981-15-6407-9_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Regulatory T cells (Tregs) are critical in maintaining immune homeostasis under various pathophysiological conditions. A growing body of evidence demonstrates that Tregs play an important role in cancer progression and that they do so by suppressing cancer-directed immune responses. Tregs have been targeted for destruction by exploiting antibodies against and small-molecule inhibitors of several molecules that are highly expressed in Tregs-including immune checkpoint molecules, chemokine receptors, and metabolites. To date, these strategies have had only limited antitumor efficacy, yet they have also created significant risk of autoimmunity because most of them do not differentiate Tregs in tumors from those in normal tissues. Currently, immune checkpoint inhibitor (ICI)-based cancer immunotherapies have revolutionized cancer treatment, but the resistance to ICI is common and the elevation of Tregs is one of the most important mechanisms. Therapeutic strategies that can selectively eliminate Tregs in the tumor (i.e. therapies that do not run the risk of causing autoimmunity by affecting normal tissue), are urgently needed for the development of cancer immunotherapies. This chapter discusses specific properties of human Tregs under the context of cancer and the various ways to target Treg for cancer immunotherapy.
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Affiliation(s)
- H Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Nicholas Borcherding
- Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
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Chen W, Xie Y, Wang M, Li C. Recent Advances on Rare Earth Upconversion Nanomaterials for Combined Tumor Near-Infrared Photoimmunotherapy. Front Chem 2020; 8:596658. [PMID: 33240857 PMCID: PMC7677576 DOI: 10.3389/fchem.2020.596658] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/07/2020] [Indexed: 01/23/2023] Open
Abstract
Cancer has been threatening the safety of human life. In order to treat cancer, many methods have been developed to treat tumor, such as traditional therapies like surgery, chemotherapy, radiotherapy, as well as new strategies like photodynamic therapy, photothermal therapy, sonodynamic therapy, and other emerging therapies. Although there are so many ways to treat tumors, these methods all face the dilemma that they are incapable to cope with metastasis and recurrence of tumors. The emergence of immunotherapy has given the hope to conquer the challenge. Immunotherapy is to use the body's own immune system to stimulate and maintain a systemic immune response to form immunological memory, resist the metastasis and recurrence of tumors. At the same time, immunotherapy can combine with other treatments to exhibit excellent antitumor effects. Upconversion nanoparticles (UCNPs) can convert near-infrared (NIR) light into ultraviolet and visible light, thus have good performance in bioimaging and NIR triggered phototherapy. In this review paper, we summarize the design, fabrication, and application of UCNPs-based NIR photoimmunotherapy for combined cancer treatment, as well as put forward the prospect of future development.
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Affiliation(s)
- Weilin Chen
- Institute of Frontier and Interdisciplinarity Science, Institute of Molecular Sciences and Engineering, Shandong University, Qingdao, China
| | - Yulin Xie
- Institute of Frontier and Interdisciplinarity Science, Institute of Molecular Sciences and Engineering, Shandong University, Qingdao, China
| | - Man Wang
- Institute of Frontier and Interdisciplinarity Science, Institute of Molecular Sciences and Engineering, Shandong University, Qingdao, China
| | - Chunxia Li
- Institute of Frontier and Interdisciplinarity Science, Institute of Molecular Sciences and Engineering, Shandong University, Qingdao, China
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Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020; 20:651-668. [PMID: 32433532 PMCID: PMC7238960 DOI: 10.1038/s41577-020-0306-5] [Citation(s) in RCA: 2568] [Impact Index Per Article: 513.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2020] [Indexed: 02/06/2023]
Abstract
The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.
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Affiliation(s)
- Alex D Waldman
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jill M Fritz
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Michael J Lenardo
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
- Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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CTLA-4 rs231775 and risk of acute renal graft rejection: an updated meta-analysis with trial sequential analysis. Sci Rep 2020; 10:12850. [PMID: 32732985 PMCID: PMC7393166 DOI: 10.1038/s41598-020-69849-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 07/21/2020] [Indexed: 01/19/2023] Open
Abstract
Contrasting results exist on the association between CTLA-4 rs231775 and acute rejection in kidney transplant recipients. We herein conducted an updated systematic review with meta-analysis and trial sequential analysis (TSA) to clarify this relationship and to establish whether the current evidence is sufficient to draw firm conclusions. In addition, noteworthiness of significant pooled odds ratios (ORs) was estimated by false positive report probability (FPRP). A comprehensive search was performed through PubMed, Web of Knowledge, Cochrane Library and Open Grey up to October 2019. Fifteen independent cohorts, including a total of 5,401 kidney transplant recipients, were identified through the systematic review. Overall, no association was detected with the allelic (OR 1.07, 95% CI 0.88-1.30, P = 0.49), dominant (OR 0.94, 95% CI 0.73-1.22, P = 0.66) or the recessive (OR 1.18, 95% CI 0.97-1.43, P = 0.096) model of CTLA-4 rs231775. In each genetic model, the cumulative Z-curve in TSA crossed the futility boundary and entered the futility area. In addition, none of the significant genetic comparisons detected in the subsequent and sensitivity analyses or in previously reported meta-analyses were found to be noteworthy by FPRP. In conclusion, this study provides strong evidence that CTLA-4 rs231775 is not a clinically-relevant genetic risk determinant of acute rejection after renal transplantation.
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Melaiu O, Lucarini V, Giovannoni R, Fruci D, Gemignani F. News on immune checkpoint inhibitors as immunotherapy strategies in adult and pediatric solid tumors. Semin Cancer Biol 2020; 79:18-43. [PMID: 32659257 DOI: 10.1016/j.semcancer.2020.07.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 06/19/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023]
Abstract
Immune checkpoint inhibitors (ICIs) have shown unprecedented benefits in various adult cancers, and this success has prompted the exploration of ICI therapy even in childhood malignances. Although the use of ICIs as individual agents has achieved disappointing response rates, combinational therapies are likely to promise better results. However, only a subset of patients experienced prolonged clinical effects, thus suggesting the need to identify robust bio-markers that predict individual clinical response or resistance to ICI therapy as the main challenge. In this review, we focus on how the use of ICIs in adult cancers can be translated into pediatric malignances. We discuss the physiological mechanism of action of each IC, including PD-1, PD-L1 and CTLA-4 and the new emerging ones, LAG-3, TIM-3, TIGIT, B7-H3, BTLA and IDO-1, and evaluate their prognostic value in both adult and childhood tumors. Furthermore, we offer an overview of preclinical models and clinical trials currently under investigation to improve the effectiveness of cancer immunotherapies in these patients. Finally, we outline the main predictive factors that influence the efficacy of ICIs, in order to lay the basis for the development of a pan-cancer immunogenomic model, able to direct young patients towards more specific immunotherapy.
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Affiliation(s)
- Ombretta Melaiu
- Paediatric Haematology/Oncology Department, Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Valeria Lucarini
- Paediatric Haematology/Oncology Department, Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | | | - Doriana Fruci
- Paediatric Haematology/Oncology Department, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
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Wang G, Tai R, Wu Y, Yang S, Wang J, Yu X, Lei L, Shan Z, Li N. The expression and immunoregulation of immune checkpoint molecule VISTA in autoimmune diseases and cancers. Cytokine Growth Factor Rev 2020; 52:1-14. [DOI: 10.1016/j.cytogfr.2020.02.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 02/02/2020] [Accepted: 02/03/2020] [Indexed: 12/24/2022]
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Galon J, Bruni D. Tumor Immunology and Tumor Evolution: Intertwined Histories. Immunity 2020; 52:55-81. [PMID: 31940273 DOI: 10.1016/j.immuni.2019.12.018] [Citation(s) in RCA: 374] [Impact Index Per Article: 74.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 07/01/2019] [Accepted: 12/20/2019] [Indexed: 12/11/2022]
Abstract
Cancer is a complex disease whose outcome depends largely on the cross-talk between the tumor and its microenvironment. Here, we review the evolution of the field of tumor immunology and the advances, in lockstep, of our understanding of cancer as a disease. We discuss the involvement of different immune cells at distinct stages of tumor progression and how immune contexture determinants shaping tumor development are being exploited therapeutically. Current clinical stratification schemes focus on the tumor histopathology and the molecular characteristics of the tumor cell. We argue for the importance of revising these stratification systems to include immune parameters so as to address the immediate need for improved prognostic and/or predictive information to guide clinical decisions.
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Affiliation(s)
- Jérôme Galon
- INSERM, Laboratory of Integrative Cancer Immunology, Equipe Labellisée Ligue Contre le Cancer, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Université de Paris; Centre de Recherche des Cordeliers, F-75006 Paris, France.
| | - Daniela Bruni
- INSERM, Laboratory of Integrative Cancer Immunology, Equipe Labellisée Ligue Contre le Cancer, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Université de Paris; Centre de Recherche des Cordeliers, F-75006 Paris, France
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Hosseini A, Gharibi T, Marofi F, Babaloo Z, Baradaran B. CTLA-4: From mechanism to autoimmune therapy. Int Immunopharmacol 2020; 80:106221. [PMID: 32007707 DOI: 10.1016/j.intimp.2020.106221] [Citation(s) in RCA: 174] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/15/2020] [Accepted: 01/15/2020] [Indexed: 12/16/2022]
Abstract
CD28 and CTLA-4 are both important stimulatory receptors for the regulation of T cell activation. Because receptors share common ligands, B7.1 and B7.2, the expression and biological function of CTLA-4 is important for the negative regulation of T cell responses. Therefore, elimination of CTLA-4 can result in the breakdown of immune tolerance and the development of several diseases such as autoimmunity. Inhibitory signals of CTLA-4 suppress T cell responses and protect against autoimmune diseases in many ways. In this review, we summarize the structure, expression and signaling pathway of CTLA-4. We also highlight how CTLA-4 defends against potentially self-reactive T cells. Finally, we discuss how the CTLA-4 regulates a number of autoimmune diseases that indicate manipulation of this inhibitory molecule is a promise as a strategy for the immunotherapy of autoimmune diseases.
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Affiliation(s)
- Arezoo Hosseini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faroogh Marofi
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Babaloo
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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40
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Hu Y, Zeng T, Xiao Z, Hu Q, Li Y, Tan X, Yue H, Wang W, Tan H, Zou J. Immunological role and underlying mechanisms of B7-H6 in tumorigenesis. Clin Chim Acta 2020; 502:191-198. [PMID: 31904350 DOI: 10.1016/j.cca.2019.12.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/31/2019] [Accepted: 12/31/2019] [Indexed: 02/07/2023]
Abstract
B7 homolog 6 (B7-H6) has been identified as involved in tumorigenesis. Elucidating its role and potential mechanism of action is essential for understanding tumorigenesis and the potential development of an effective clinical strategy. Abnormal overexpression of B7-H6 in various types of tumors was reported to be linked with poor prognosis. B7-H6 suppresses the initiation of the "caspase cascade" and induces anti-apoptosis by STAT3 pathway activation to provoke tumorigenesis. B7-H6 facilitates tumor proliferation and cell cycle progression by regulating apoptosis suppressors. B7-H6 induces cellular cytotoxicity, secretion of TNF-α and IFN-γ and B7-H6-specific BiTE triggers T cells to accelerate tumorigenesis. B7-H6 induces abnormal immunological progression by HER2-scFv mediated ADCC and NKp30 immune escape to promote tumorigenesis. B7-H6 promotes tumorigenesis via apoptosis inhibition, proliferation and immunological progression. B7-H6 may a valuable potential biomarker and therapeutic strategy for diagnostics, prognostics and treatment in cancer.
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Affiliation(s)
- Yuxuan Hu
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China
| | - Tian Zeng
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China
| | - Zheng Xiao
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China
| | - Qihao Hu
- Cardiothoracic Surgery, The Second Affiliated Hospital, University of South China, Hengyang, Hunan 421001, PR China
| | - Yukun Li
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China
| | - Xiongjin Tan
- The Second Department of Orthopaedic, 922 Hospital of PLA, Hengyang, Hunan 410011, PR China
| | - Haiyan Yue
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Department of Pathology, The Central Hospital of Shaoyang, Shaoyang, Hunan 422000, PR China
| | - Wensong Wang
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China
| | - Hui Tan
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China.
| | - Juan Zou
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China.
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Mitsuiki N, Schwab C, Grimbacher B. What did we learn from CTLA-4 insufficiency on the human immune system? Immunol Rev 2019; 287:33-49. [PMID: 30565239 DOI: 10.1111/imr.12721] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 09/16/2018] [Indexed: 02/07/2023]
Abstract
Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA-4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA-4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA-4-mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA-4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty-eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA-4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA-4-insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA-4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life-threatening, treatment-resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA-4 insufficiency causes severe disease taught us that the amount of CTLA-4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology-causing activated T lymphocytes in CTLA-4-insufficient patients are antigen-specific is an unsolved question. CTLA-4, in addition, has a role in autoimmune diseases and cancer. Anti-CTLA-4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA-4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA-4 molecule and immune dysregulation disorders.
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Affiliation(s)
- Noriko Mitsuiki
- Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Charlotte Schwab
- Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bodo Grimbacher
- Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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42
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Watanabe A, Inoue N, Watanabe M, Yamamoto M, Ozaki H, Hidaka Y, Iwatani Y. Increases of CD80 and CD86 Expression on Peripheral Blood Cells and their Gene Polymorphisms in Autoimmune Thyroid Disease. Immunol Invest 2019; 49:191-203. [DOI: 10.1080/08820139.2019.1688343] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Ayano Watanabe
- Department of Biomedical Informatics Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoya Inoue
- Department of Biomedical Informatics Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
- Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan
| | - Mikio Watanabe
- Department of Biomedical Informatics Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Mayu Yamamoto
- Department of Biomedical Informatics Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Haruka Ozaki
- Department of Biomedical Informatics Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoh Hidaka
- Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan
| | - Yoshinori Iwatani
- Department of Biomedical Informatics Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
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43
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A significant association of the CTLA4 gene variants with the risk of autoimmune Graves' disease in ethnic Kashmiri population. Cell Immunol 2019; 347:103995. [PMID: 31708111 DOI: 10.1016/j.cellimm.2019.103995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/08/2019] [Accepted: 10/19/2019] [Indexed: 01/03/2023]
Abstract
Graves' disease (GD) is the commonest cause of hyperthyroidism in populations with adequate iodine intake. It results from an abnormality in the immune system, which produces unique antibodies causing over production of thyroid hormones and glandular hyperplasia in individuals with genetic susceptibility. The Cytotoxic Lymphocyte Associated Antigen-4 (CTLA4) gene product serves the important function of immunomodulation, thereby helping in maintenance of peripheral self-tolerance. Studies on the association of the CTLA4 SNPs with GD have shown variations in the results from different populations. Since no such study has been carried out in ethnic Kashmiri population, we aimed to study a possible association of the CTLA4 SNPs (+49 A/G, -318C/T, CT 60 A/G and -1661 A/G) with GD. A total of 285 individuals (135 patients with GD and 150 healthy individuals) were genotyped using PCR-RFLP method and the results showed statistically significant differences in genotypic and allelic frequencies of cases and controls for + 49 A/G SNP (p=<0.001; OR = 5.14; CI = 2.17-12.19) and CT 60 A/G SNP (p = < 0.001; OR = 6.9; CI = 2.8-16.6), while -318C/T and -1661 A/G SNPs showed no significant association. We also studied the mRNA expression of the CTLA4 in patients with GD and healthy individuals by Real-Time PCR and found a decreased expression of the CTLA4 mRNA in PBMCs of patients with GD as compared to healthy controls with a -3.71-fold change. We conclude that the CTLA4 + 49 A/G and CT 60 A/G SNPs have a significant association with the risk of GD development in Kashmiri population and CTLA4 mRNA expression is significantly decreased in GD.
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44
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Li B, Chan HL, Chen P. Immune Checkpoint Inhibitors: Basics and Challenges. Curr Med Chem 2019; 26:3009-3025. [PMID: 28782469 DOI: 10.2174/0929867324666170804143706] [Citation(s) in RCA: 307] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 04/26/2017] [Accepted: 07/25/2017] [Indexed: 12/15/2022]
Abstract
Cancer is one of the most deadly diseases in the modern world. The last decade has witnessed dramatic advances in cancer treatment through immunotherapy. One extremely promising means to achieve anti-cancer immunity is to block the immune checkpoint pathways - mechanisms adopted by cancer cells to disguise themselves as regular components of the human body. Many review articles have described a variety of agents that are currently under extensive clinical evaluation. However, while checkpoint blockade is universally effective against a broad spectrum of cancer types and is mostly unrestricted by the mutation status of certain genes, only a minority of patients achieve a complete response. In this review, we summarize the basic principles of immune checkpoint inhibitors in both antibody and smallmolecule forms and also discuss potential mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for these inhibitors.
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Affiliation(s)
- Bin Li
- University of Miami, Miller School of Medicine, Miami, Florida 33156, United States
| | - Ho Lam Chan
- University of Miami, Miller School of Medicine, Miami, Florida 33156, United States
| | - Pingping Chen
- University of Miami, Miller School of Medicine, Miami, Florida 33156, United States
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45
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The role of immune regulatory molecules in multiple sclerosis. J Neuroimmunol 2019; 337:577061. [PMID: 31520791 DOI: 10.1016/j.jneuroim.2019.577061] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/04/2019] [Accepted: 09/04/2019] [Indexed: 12/14/2022]
Abstract
Multiple sclerosis (MS) is the most common demyelinating disease which mainly impacts the integrity of central nervous system (CNS). MS etiology is not clearly known but genetic, environmental factors and immune system are the most frequently explored risk factors. Adaptive immune responses have a critical role in MS pathogenesis in which auto-reactive T-cells and autoantibodies are main orchestrators. Immune responses are modulated by inhibitory molecules which regulates adaptive system activation and hemostasis interface. These molecules suppress immune responses through inhibition of cytokine secretion and T cell proliferation and subsequently reducing the inflammation and respective damage. Therefore the critical role of inhibitory molecules in regulating the healthy and safe immune responses make them very attractive target for immunotherapy. In this review paper, the role of inhibitory molecules expressed on the various immune cell types in MS pathogenesis and experimental autoimmune encephalomyelitis (EAE) animal model will be summarized.
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46
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Kailashiya V, Sharma HB, Kailashiya J. Role of CTLA4 A49G polymorphism in systemic lupus erythematosus and its geographical distribution. J Clin Pathol 2019; 72:659-662. [DOI: 10.1136/jclinpath-2019-206013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/03/2019] [Accepted: 07/11/2019] [Indexed: 01/15/2023]
Abstract
CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes. Its inhibitory function promotes long-lived anergy in immune cells and prevents autoimmunity. Therefore, it plays a crucial role in T cell-mediated autoimmunity, and thus in susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). It is encoded by CTLA4 gene in humans. AtoG polymorphism at position +49 of CTLA4 gene is the only polymorphism which changes amino acid sequence from alanine to threonine in the leader sequence, which may affect the function of CTLA-4. Association of CTLA4 polymorphisms with SLE has been investigated in several reports in different ethnic populations from different countries, which have shown highly inconsistent findings. In this review, we have compiled previous studies which have reported the association of CTLA4 A49G polymorphism in SLE and its geographical distribution.
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Pinto JA, Raez LE, Oliveres H, Rolfo CC. Current knowledge of Ipilimumab and its use in treating non-small cell lung cancer. Expert Opin Biol Ther 2019; 19:509-515. [DOI: 10.1080/14712598.2019.1610380] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Joseph A. Pinto
- Unidad de Investigación Básica y Traslacional, Oncosalud-AUNA, Lima, Perú
| | - Luis E. Raez
- Thoracic Oncology Program, Memorial Cancer Institute/Memorial Health Care System, Florida International University, Miami, USA
| | - Helena Oliveres
- Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Antwerp, Belgium
| | - Christian C. Rolfo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
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48
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Lingel H, Brunner-Weinzierl MC. CTLA-4 (CD152): A versatile receptor for immune-based therapy. Semin Immunol 2019; 42:101298. [DOI: 10.1016/j.smim.2019.101298] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/05/2019] [Indexed: 12/31/2022]
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49
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Chang LS, Barroso-Sousa R, Tolaney SM, Hodi FS, Kaiser UB, Min L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr Rev 2019; 40:17-65. [PMID: 30184160 PMCID: PMC6270990 DOI: 10.1210/er.2018-00006] [Citation(s) in RCA: 336] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 06/07/2018] [Indexed: 12/13/2022]
Abstract
Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.
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Affiliation(s)
- Lee-Shing Chang
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Romualdo Barroso-Sousa
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - F Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Ursula B Kaiser
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Le Min
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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50
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Abstract
Immune responses are controlled by the optimal balance between protective immunity and immune tolerance. T-cell receptor (TCR) signals are modulated by co-signaling molecules, which are divided into co-stimulatory and co-inhibitory molecules. By expression at the appropriate time and location, co-signaling molecules positively and negatively control T-cell differentiation and function. For example, ligation of the CD28 on T cells provides a critical secondary signal along with TCR ligation for naive T-cell activation. In contrast, co-inhibitory signaling by the CD28-B7 family is important to regulate immune homeostasis and host defense, as these signals limit the strength and duration of immune responses to prevent autoimmunity. At the same time, microorganisms or tumor cells can use these pathways to establish an immunosuppressive environment to inhibit the immune responses against themselves. Understanding these co-inhibitory pathways will support the development of new immunotherapy for the treatment of tumors and autoimmune and infectious diseases. Here, we introduce diverse molecules belonging to the members of the CD28-B7 family.
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