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Rezayat F, Esmaeil N, Nikpour P, Feizi A, Rezaei A. Different behavior of NK cells isolated from healthy women and women with recurrent spontaneous abortion after treatment with human amniotic epithelial cells. J Leukoc Biol 2025; 117:qiaf020. [PMID: 40276927 DOI: 10.1093/jleuko/qiaf020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 12/03/2024] [Indexed: 04/26/2025] Open
Abstract
Maternal immunotolerance during pregnancy is heavily dependent on the critical properties of human amniotic epithelial cells (hAECs). Recurrent spontaneous abortion (RSA) is one of the most common diseases in women and is caused by feto-maternal immunotolerance disruption. The objective of this study is to investigate how hAEECs affect pNK cells isolated from RSA and healthy women in terms of immunomodulation. Peripheral blood NK cells were isolated from 20 women with RSA and 20 healthy women. Purified NK cells were co-cultured with hAECs, obtained from full-term healthy pregnant women at different cellular ratios. After 24 and 72 h of incubation, the expression of immunomodulatory genes in hAECs, immunophenotype, and cytotoxicity of NK cells, and cytokine production were investigated using real-time PCR, flow cytometry, and ELISA techniques, respectively. We observed a significant increase in TGF-β and IL-10 production, and CD56bright CD16+ subpopulation in pNK cells, a significant decrease in IFN-γ production and CD107a and FasL expression on NK cells. Also, NK cells' cytotoxicity against K562 cells was diminished after co-culture with hAECs. The expression of TGF-β and HLA-G genes by hAECs was diminished after co-culture with NK cells isolated from women with RSA. Our research indicates that the interaction between NK cells and hAECs influences the phenotype and function of both cells. Also, NK cells belonging to women with RSA and healthy women exhibit different behavior during treatment with hAECs, possibly due to NK cell dysfunction. However, extensive research is required to assess NK cell defects and their mutual interaction with hAECs.
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Affiliation(s)
- Fatemeh Rezayat
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan 8174673461, Iran
| | - Nafiseh Esmaeil
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan 8174673461, Iran
- Pooya Zist-Mabna Hakim Company, Isfahan Health Center, Aghababaei Highway, Isfahan 8159611119, Iran
| | - Parvaneh Nikpour
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan 8174673461, Iran
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Post box 100 405 30, Gothenburg, Sweden
| | - Awat Feizi
- Department of Epidemiology and Biostatistics, Isfahan Endocrine and Metabolism Research Center, School of Public Health, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan 8174673461, Iran
| | - Abbas Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan 8174673461, Iran
- Immunodeficiency Diseases Research Center, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan 8174673461, Iran
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Gu B, Ferreira LMR, Herrera S, Brown L, Lieberman J, Sherwood RI, Meissner TB, Strominger JL. The TEA domain transcription factors TEAD1 and TEAD3 and WNT signaling determine HLA-G expression in human extravillous trophoblasts. Proc Natl Acad Sci U S A 2025; 122:e2425339122. [PMID: 40096597 PMCID: PMC11962456 DOI: 10.1073/pnas.2425339122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 02/04/2025] [Indexed: 03/19/2025] Open
Abstract
Maternal-fetal immune tolerance guarantees a successful pregnancy throughout gestation. HLA-G, a nonclassical human leukocyte antigen (HLA) molecule exclusively expressed in extravillous trophoblasts (EVT), is a crucial factor in establishing maternal-fetal immune tolerance by interacting with inhibitory receptors on various maternal immune cells residing in the uterus. While trophoblast-specific cis-regulatory elements impacting HLA-G transcription have been described, the identity of trans-acting factors controlling HLA-G expression in EVT remains poorly understood. Utilizing a genome-wide CRISPR-Cas9 knockout screen, we find that the WNT signaling pathway negatively regulates HLA-G expression in EVT. In addition, we identified two trophoblast-specific transcription factors, TEAD1 and TEAD3, required for HLA-G transcription in EVT in a Yes-associated protein-independent manner. Altogether, we systematically elucidated essential genes and pathways underlying HLA-G expression in EVT, shedding light on the mechanisms of maternal-fetal tolerance and potentially providing insights into controlling HLA-G expression beyond EVT to protect allogeneic cells from immune rejection.
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Affiliation(s)
- Bowen Gu
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA02138
- Program in Cellular and Molecular Medicine Boston Children’s Hospital, Boston, MA02115
- Department of Pediatrics, Harvard Medical School, Boston, MA02115
| | - Leonardo M. R. Ferreira
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC29425
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC29425
- Cancer Biology and Immunology Program, Hollings Cancer Center, Charleston, SC29425
| | - Sebastian Herrera
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA02138
| | - Lara Brown
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital Harvard Medical School, Boston, MA02115
| | - Judy Lieberman
- Program in Cellular and Molecular Medicine Boston Children’s Hospital, Boston, MA02115
- Department of Pediatrics, Harvard Medical School, Boston, MA02115
| | - Richard I. Sherwood
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital Harvard Medical School, Boston, MA02115
| | - Torsten B. Meissner
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA02215
- Department of Surgery, Harvard Medical School, Boston, MA02115
| | - Jack L. Strominger
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA02138
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Kim J, Park S, Kim J, Kim Y, Yoon HM, Rayhan BR, Jeong J, Bothwell ALM, Shin JH. Trogocytosis-mediated immune evasion in the tumor microenvironment. Exp Mol Med 2025; 57:1-12. [PMID: 39741180 PMCID: PMC11799389 DOI: 10.1038/s12276-024-01364-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 01/02/2025] Open
Abstract
Trogocytosis is a dynamic cellular process characterized by the exchange of the plasma membrane and associated cytosol during cell-to-cell interactions. Unlike phagocytosis, this transfer maintains the surface localization of transferred membrane molecules. For example, CD4 T cells engaging with antigen-presenting cells undergo trogocytosis, which facilitates the transfer of antigen-loaded major histocompatibility complex (MHC) class II molecules from antigen-presenting cells to CD4 T cells. This transfer results in the formation of antigen-loaded MHC class II molecule-dressed CD4 T cells. These "dressed" CD4 T cells subsequently participate in antigen presentation to other CD4 T cells. Additionally, trogocytosis enables the acquisition of immune-regulatory molecules, such as CTLA-4 and Tim3, in recipient cells, thereby modulating their anti-tumor immunity. Concurrently, donor cells undergo plasma membrane loss, and substantial loss can trigger trogocytosis-mediated cell death, termed trogoptosis. This review aims to explore the trogocytosis-mediated transfer of immune regulatory molecules and their implications within the tumor microenvironment to elucidate the underlying mechanisms of immune evasion in cancers.
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Affiliation(s)
- Jeonghyun Kim
- Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Korea
| | - Soyeon Park
- Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Korea
| | - Jungseo Kim
- Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea
| | - Yewon Kim
- Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea
| | - Hong Min Yoon
- Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea
| | - Bima Rexa Rayhan
- Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea
| | - Jaekwang Jeong
- Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Alfred L M Bothwell
- Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, 505 S. 45th Street, Omaha, NE, 68198, USA.
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA.
| | - Jae Hun Shin
- Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Korea.
- Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, 21983, Korea.
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Benitez Fuentes JD, Bartolome Arcilla J, Mohamed Mohamed K, Lopez de Sa A, de Luna Aguilar A, Guevara-Hoyer K, Ballestin Martinez P, Lazaro Sanchez AD, Carosella ED, Ocaña A, Sánchez-Ramon S. Targeting of Non-Classical Human Leukocyte Antigens as Novel Therapeutic Strategies in Cancer. Cancers (Basel) 2024; 16:4266. [PMID: 39766165 PMCID: PMC11675049 DOI: 10.3390/cancers16244266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/09/2024] [Accepted: 12/14/2024] [Indexed: 01/11/2025] Open
Abstract
Human leukocyte antigens (HLAs) are essential regulators of immune responses against cancer, with classical HLAs well-documented for their role in tumor recognition and immune surveillance. In recent years, non-classical HLAs-including HLA-E, HLA-F, HLA-G, and HLA-H-have emerged as critical players in the immune landscape of cancer due to their diverse and less conventional functions in immune modulation. These molecules exhibit unique mechanisms that enable tumors to escape immune detection, promote tumor progression, and contribute to therapeutic resistance. This review provides a comprehensive examination of the current understanding of non-classical HLAs in solid cancers, focusing on their specific roles in shaping the tumor microenvironment and influencing immune responses. By analyzing how HLA-E, HLA-F, HLA-G, and HLA-H modulate interactions with immune cells, such as T cells, natural killer cells, and antigen-presenting cells, we highlight key pathways through which these molecules contribute to immune evasion and metastasis. Additionally, we review promising therapeutic strategies aimed at targeting non-classical HLAs, including emerging immunotherapies that could potentially enhance cancer treatment outcomes by reversing immune suppression within tumors. Understanding the influence of these non-classical HLAs in solid cancers may offer new insights into cancer immunology and may lead to the development of innovative and more effective immunotherapeutic approaches. This review underscores the importance of non-classical HLAs as potential therapeutic targets, providing a necessary foundation for future studies in the evolving field of cancer immunotherapy.
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Affiliation(s)
| | - Jorge Bartolome Arcilla
- Department of Medical Oncology, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (J.B.A.); (A.L.d.S.); (P.B.M.)
- Experimental Therapeutics in Cancer Unit, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain
| | - Kauzar Mohamed Mohamed
- Department of Immunology, IML and IdISSC, Hospital Clinico San Carlos, 28040 Madrid, Spain; (K.M.M.); (K.G.-H.); (S.S.-R.)
| | - Alfonso Lopez de Sa
- Department of Medical Oncology, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (J.B.A.); (A.L.d.S.); (P.B.M.)
| | - Alicia de Luna Aguilar
- Department of Medical Oncology, Hospital General Universitario Morales Meseguer, 30008 Murcia, Spain;
| | - Kissy Guevara-Hoyer
- Department of Immunology, IML and IdISSC, Hospital Clinico San Carlos, 28040 Madrid, Spain; (K.M.M.); (K.G.-H.); (S.S.-R.)
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, 28040 Madrid, Spain
| | - Pablo Ballestin Martinez
- Department of Medical Oncology, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (J.B.A.); (A.L.d.S.); (P.B.M.)
- Department of Medical Oncology, Hospital 12 de Octubre, 28041 Madrid, Spain
| | | | - Edgardo D. Carosella
- CEA, DRF-Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, 75010 Paris, France;
- U976 HIPI Unit, IRSL, Université Paris, 75006 Paris, France
| | - Alberto Ocaña
- Department of Medical Oncology, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (J.B.A.); (A.L.d.S.); (P.B.M.)
- Experimental Therapeutics in Cancer Unit, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain
- START Madrid-Fundación Jiménez Díaz (FJD) Early Phase Program, Fundación Jiménez Díaz Hospital, 28040 Madrid, Spain
| | - Silvia Sánchez-Ramon
- Department of Immunology, IML and IdISSC, Hospital Clinico San Carlos, 28040 Madrid, Spain; (K.M.M.); (K.G.-H.); (S.S.-R.)
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, 28040 Madrid, Spain
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Karczmarczyk A, Chojnacki M, Paziewska M, Karp M, Skórka K, Zaleska J, Purkot J, Własiuk P, Giannopoulos K. HLA-G can be transfered via trogocytosis from leukemic cells to T cells in chronic lymphocytic leukemia. Hum Immunol 2024; 85:111178. [PMID: 39541623 DOI: 10.1016/j.humimm.2024.111178] [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: 07/22/2024] [Revised: 10/21/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
In chronic lymphocytic leukemia (CLL) immune escape mechanism allows leukemia cells to proliferate and expand and it might also be responsible for disease progression. Some molecules involved in the regulation of an immune system might represent prognostic value for CLL patients. Among numerous immune escape mechanisms it was shown that the expression of human leukocyte antigen G (HLA-G) might represent one of the agents damaging cellular immune response. In the present study, the expression of the HLA-G molecule and ILT-2 receptor on the surface of leukemic cells, as well as a plasma concentration of soluble HLA-G (sHLA-G) was evaluated. Also, we investigated whether HLA-G could be transferred from leukemic cells to T cells by the mechanism of trogocytosis. We showed higher proportion of leukemic cells expressing HLA-G and increased levels of sHLA-G in CLL patients compared to that of B-cells in healthy volunteers (HVs). Results of our work showed a time-dependent increase in HLA-G expression on CD4+ T cells co-incubated with HLA-G-positive CD19+ cells. Longer coincubation times did significantly increase these proportions (p < 0.001). We have shown that a higher proportion of HLA-G-expressing CD4+ T cells correlated with the clinical stage of the disease according to the Rai classification. Interestingly, we found a higher CD4+HLA-G+ percentage in the group with unmutated immunoglobulin heavy chain variable region (IGHV) genes compared to the group with mutated IGHV gene after 48 h co-culture. In summary, increasing evidence has revealed that, in addition to HLA-G expressed on tumor cells, intercellular transfer of HLA-G among cancer cells and immune cells through trogocytosis plays important roles in mechanism of immune escape, disease progression and poor clinical outcome.
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MESH Headings
- Humans
- HLA-G Antigens/genetics
- HLA-G Antigens/immunology
- HLA-G Antigens/metabolism
- HLA-G Antigens/blood
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Male
- Middle Aged
- Aged
- Female
- Tumor Escape
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Coculture Techniques
- Antigens, CD19/metabolism
- Antigens, CD19/immunology
- Adult
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- Leukocyte Immunoglobulin-like Receptor B1/metabolism
- Aged, 80 and over
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/genetics
- Antigens, CD
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Affiliation(s)
| | - Michał Chojnacki
- Department of Medical Biology, Institute of Rural Health, Lublin, Poland
| | - Magdalena Paziewska
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland
| | - Marta Karp
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland
| | - Katarzyna Skórka
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland
| | - Joanna Zaleska
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland
| | - Joanna Purkot
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland
| | - Paulina Własiuk
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland
| | - Krzysztof Giannopoulos
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland.
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Chen Y, Xin Q, Zhu M, Qiu J, Qiu J, Li R, Tu J. Trogocytosis in CAR immune cell therapy: a key mechanism of tumor immune escape. Cell Commun Signal 2024; 22:521. [PMID: 39468646 PMCID: PMC11514842 DOI: 10.1186/s12964-024-01894-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 10/15/2024] [Indexed: 10/30/2024] Open
Abstract
Immune cell therapy based on chimeric antigen receptor (CAR) technology platform has been greatly developed. The types of CAR immune cell therapy have expanded from T cells to innate immune cells such as NK cells and macrophages, and the diseases treated have expanded from hematological malignancies to non-tumor fields such as infectious diseases and autoimmune diseases. Among them, CAR-T and CAR-NK therapy have observed examples of rapid remission in approved clinical trials, but the efficacy is unstable and plagued by tumor resistance. Trogocytosis is a special phenomenon of intercellular molecular transfer that is common in the immune system and is achieved by recipient cells through acquisition and internalization of donor cell-derived molecules and mediates immune effects. Recently, a novel short-term drug resistance mechanism based on trogocytosis has been proposed, and the bidirectional molecular exchange between CAR immune cells and tumor cells triggered by trogocytosis partially explains the long-term relapse phenomenon after treatment with CAR immune cells. In this review, we summarize the research progress of trogocytosis in CAR immunotherapy, discuss the influencing factors of trogocytosis and its direct and indirect interference with CAR immune cells and emphasize that the interference of trogocytosis can further release the potential of CAR immune cell therapy.
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Affiliation(s)
- Yizhao Chen
- Department of Pharmacy, Hefei First People's Hospital, The Third Affiliated Hospital of Anhui Medical University, 390# Huaihe Road, Luyang District, Hefei, China
| | - Qianling Xin
- Anhui Women and Children's Medical Center, Hefei Maternal and Child Health Hospital, Hefei, China
| | - Mengjuan Zhu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, 81# Meishan Road, Shushan District, Hefei, China
| | - Jiaqi Qiu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, 81# Meishan Road, Shushan District, Hefei, China
| | - Ji Qiu
- Department of Pharmacy, Hefei First People's Hospital, The Third Affiliated Hospital of Anhui Medical University, 390# Huaihe Road, Luyang District, Hefei, China.
| | - Ruilin Li
- Department of Pharmacy, Hefei First People's Hospital, The Third Affiliated Hospital of Anhui Medical University, 390# Huaihe Road, Luyang District, Hefei, China.
| | - Jiajie Tu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, 81# Meishan Road, Shushan District, Hefei, China.
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Coënon L, Geindreau M, Ghiringhelli F, Villalba M, Bruchard M. Natural Killer cells at the frontline in the fight against cancer. Cell Death Dis 2024; 15:614. [PMID: 39179536 PMCID: PMC11343846 DOI: 10.1038/s41419-024-06976-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024]
Abstract
Natural Killer (NK) cells are innate immune cells that play a pivotal role as first line defenders in the anti-tumor response. To prevent tumor development, NK cells are searching for abnormal cells within the body and appear to be key players in immunosurveillance. Upon recognition of abnormal cells, NK cells will become activated to destroy them. In order to fulfill their anti-tumoral function, they rely on the secretion of lytic granules, expression of death receptors and production of cytokines. Additionally, NK cells interact with other cells in the tumor microenvironment. In this review, we will first focus on NK cells' activation and cytotoxicity mechanisms as well as NK cells behavior during serial killing. Lastly, we will review NK cells' crosstalk with the other immune cells present in the tumor microenvironment.
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Affiliation(s)
- Loïs Coënon
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Mannon Geindreau
- Equipe TIRECs, Labellisée Ligue Contre le Cancer, Centre de Recherche INSERM CTM-UMR1231, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
| | - François Ghiringhelli
- Equipe TIRECs, Labellisée Ligue Contre le Cancer, Centre de Recherche INSERM CTM-UMR1231, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
- Platform of Transfer in Biological Oncology, Georges-François Leclerc Cancer Center, Dijon, France
| | - Martin Villalba
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France
- Institut du Cancer Avignon-Provence Sainte Catherine, Avignon, France
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Mélanie Bruchard
- Equipe TIRECs, Labellisée Ligue Contre le Cancer, Centre de Recherche INSERM CTM-UMR1231, Dijon, France.
- University of Bourgogne Franche-Comté, Dijon, France.
- Platform of Transfer in Biological Oncology, Georges-François Leclerc Cancer Center, Dijon, France.
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8
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Seliger B. Role of HLA-G in tumors and upon COVID-19 infection. Hum Immunol 2024; 85:110792. [PMID: 38555250 DOI: 10.1016/j.humimm.2024.110792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/07/2024] [Accepted: 03/25/2024] [Indexed: 04/02/2024]
Abstract
HLA-G expression of tumors and upon viral infections is involved in their immune escape leading to the evasion from both T and NK cell recognition. The underlying mechanisms of HLA-G expression in both pathophysiologic conditions are broad and range from genetic abnormalities to epigenetic, transcriptional and posttranscriptional regulation. This review summarizes the current knowledge of the frequency, regulation and clinical relevance of HLA-G expression upon neoplastic and viral transformation, its interaction with components of the microenvironment as well as its potential as diagnostic marker and/or therapeutic target. In addition, it discusses urgent topics, which have to be addressed in HLA-G research.
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Affiliation(s)
- Barbara Seliger
- Institute of Translational Immunology, Medical School "Theodor Fontane", 14770, Brandenburg an der Havel, Germany; Medical Faculty, Martin Luther University Halle-Wittenberg, 06112, Halle (Saale), Germany; Fraunhofer Institute for Cell Therapy and Immunology, 04103, Leipzig, Germany.
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9
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Wang S, Wang J, Xia Y, Zhang L, Jiang Y, Liu M, Gao Q, Zhang C. Harnessing the potential of HLA-G in cancer therapy: advances, challenges, and prospects. J Transl Med 2024; 22:130. [PMID: 38310272 PMCID: PMC10838004 DOI: 10.1186/s12967-024-04938-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/27/2024] [Indexed: 02/05/2024] Open
Abstract
Immune checkpoint blockades have been prized in circumventing and ablating the impediments posed by immunosuppressive receptors, reaching an exciting juncture to be an innovator in anticancer therapy beyond traditional therapeutics. Thus far, approved immune checkpoint blockades have principally targeted PD-1/PD-L1 and CTLA-4 with exciting success in a plethora of tumors and yet are still trapped in dilemmas of limited response rates and adverse effects. Hence, unveiling new immunotherapeutic targets has aroused immense scientific interest in the hope of expanding the clinical application of immune checkpoint blockades to scale new heights. Human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is enriched on various malignant cells and is involved in the hindrance of immune effector cells and the facilitation of immunosuppressive cells. HLA-G stands out as a crucial next-generation immune checkpoint showing great promise for the benefit of cancer patients. Here, we provide an overview of the current understanding of the expression pattern and immunological functions of HLA-G, as well as its interaction with well-characterized immune checkpoints. Since HLA-G can be shed from the cell surface or released by various cells as free soluble HLA-G (sHLA-G) or as part of extracellular vesicles (EVs), namely HLA-G-bearing EVs (HLA-GEV), we discuss the potential of sHLA-G and HLA-GEV as predictive biomarkers. This review also addresses the advancement of HLA-G-based therapies in preclinical and clinical settings, with a focus on their clinical application in cancer.
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Affiliation(s)
- Siyuan Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jiaxin Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Yu Xia
- Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Le Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Yueqiang Jiang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Man Liu
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Qinglei Gao
- Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
| | - Cuntai Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
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10
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Agbakwuru D, Wetzel SA. The Biological Significance of Trogocytosis. Results Probl Cell Differ 2024; 73:87-129. [PMID: 39242376 PMCID: PMC11784324 DOI: 10.1007/978-3-031-62036-2_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2024]
Abstract
Trogocytosis is the intercellular transfer of membrane and membrane-associated proteins between cells. Trogocytosis is an underappreciated phenomenon that has historically routinely been dismissed as an artefact. With a greater understanding of the process and the implications it has on biological systems, trogocytosis has the potential to become a paradigm changer. The presence on a cell of molecules they don't endogenously express can alter the biological activity of the cell and could also lead to the acquisition of new functions. To better appreciate this phenomenon, it is important to understand how these intercellular membrane exchanges influence the function and activity of the donor and the recipient cells. In this chapter, we will examine how the molecules acquired by trogocytosis influence the biology of a variety of systems including mammalian fertilization, treatment of hemolytic disease of the newborn, viral and parasitic infections, cancer immunotherapy, and immune modulation.
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Affiliation(s)
- Deborah Agbakwuru
- Center for Environmental Health Sciences, University of Montana, Missoula, MT, USA
| | - Scott A Wetzel
- Center for Environmental Health Sciences, University of Montana, Missoula, MT, USA.
- Division of Biological Sciences, University of Montana, Missoula, MT, USA.
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11
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Ramezani F, Panahi Meymandi AR, Akbari B, Tamtaji OR, Mirzaei H, Brown CE, Mirzaei HR. Outsmarting trogocytosis to boost CAR NK/T cell therapy. Mol Cancer 2023; 22:183. [PMID: 37974170 PMCID: PMC10652537 DOI: 10.1186/s12943-023-01894-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/03/2023] [Indexed: 11/19/2023] Open
Abstract
Chimeric antigen receptor (CAR) NK and T cell therapy are promising immunotherapeutic approaches for the treatment of cancer. However, the efficacy of CAR NK/T cell therapy is often hindered by various factors, including the phenomenon of trogocytosis, which involves the bidirectional exchange of membrane fragments between cells. In this review, we explore the role of trogocytosis in CAR NK/T cell therapy and highlight potential strategies for its modulation to improve therapeutic efficacy. We provide an in-depth analysis of trogocytosis as it relates to the fate and function of NK and T cells, focusing on its effects on cell activation, cytotoxicity, and antigen presentation. We discuss how trogocytosis can mediate transient antigen loss on cancer cells, thereby negatively affecting the effector function of CAR NK/T cells. Additionally, we address the phenomenon of fratricide and trogocytosis-associated exhaustion, which can limit the persistence and effectiveness of CAR-expressing cells. Furthermore, we explore how trogocytosis can impact CAR NK/T cell functionality, including the acquisition of target molecules and the modulation of signaling pathways. To overcome the negative effects of trogocytosis on cellular immunotherapy, we propose innovative approaches to modulate trogocytosis and augment CAR NK/T cell therapy. These strategies encompass targeting trogocytosis-related molecules, engineering CAR NK/T cells to resist trogocytosis-induced exhaustion and leveraging trogocytosis to enhance the function of CAR-expressing cells. By overcoming the limitations imposed by trogocytosis, it may be possible to unleash the full potential of CAR NK/T therapy against cancer. The knowledge and strategies presented in this review will guide future research and development, leading to improved therapeutic outcomes in the field of immunotherapy.
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Affiliation(s)
- Faezeh Ramezani
- Division of Medical Biotechnology, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Reza Panahi Meymandi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnia Akbari
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Omid Reza Tamtaji
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Christine E Brown
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA
- Department of Immuno-Oncology, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
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12
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Mao J, Feng Y, Zhu X, Ma F. The Molecular Mechanisms of HLA-G Regulatory Function on Immune Cells during Early Pregnancy. Biomolecules 2023; 13:1213. [PMID: 37627278 PMCID: PMC10452754 DOI: 10.3390/biom13081213] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 08/01/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical human major histocompatibility complex (MHC-I) molecule with the membrane-bound and soluble types. HLA-G is primarily expressed by extravillous cytotrophoblast cells located at the maternal-fetal interface during pregnancy and is essential in establishing immune tolerance. This review provides a comprehensive understanding of the multiple molecular mechanisms by which HLA-G regulates the immune function of NK cells. It highlights that HLA-G binds to microRNA to suppress NK cell cytotoxicity and stimulate the secretion of growth factors to support fetal growth. The interactions between HLA-G and NK cells also activate senescence signaling, promoting spiral artery remodeling and maintaining the balance of maternal-fetal immune responses. In addition, HLA-G can inhibit the function of decidual T cells, dendritic cells, and macrophages. Overall, the interaction between trophoblast cells and immune cells mediated by HLA-G plays a crucial role in understanding immune regulation at the maternal-fetal interface and offers insights into potential treatments for pregnancy-related diseases.
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Affiliation(s)
- Jia Mao
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China;
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, State Key Laboratory of Biotherapy and Cancer Center, College of Life Sciences, Sichuan University, Chengdu 610064, China
| | - Ying Feng
- Department of Histology, Embryology and Neurobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China;
| | - Xiaofeng Zhu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, State Key Laboratory of Biotherapy and Cancer Center, College of Life Sciences, Sichuan University, Chengdu 610064, China
| | - Fang Ma
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China;
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
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13
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Marik B, Nomani K, Agarwal N, Dadhwal V, Sharma A. Role of the HLA-G regulatory region polymorphisms in idiopathic recurrent spontaneous abortions (RSA). Am J Reprod Immunol 2023; 90:e13740. [PMID: 37491923 DOI: 10.1111/aji.13740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 04/28/2023] [Accepted: 06/10/2023] [Indexed: 07/27/2023] Open
Abstract
PROBLEM HLA-G polymorphisms have a functional impact on its expression and may cause a breakdown of maternal tolerance towards the semi-allogenic fetus, resulting in recurrent spontaneous abortions (RSA). This study reports on the association of HLA-G regulatory region polymorphisms with idiopathic RSA. METHODS Seventy-five couples with ≥2 spontaneous abortions were recruited in comparison to 75 healthy couples who had normal pregnancies. About 5 mL of blood samples were collected from all the participants, and DNA was extracted. Screening of HLA-G 5'-upstream regulatory region (5'-URR) was done by direct sequencing in 50 each of RSA and healthy couples, respectively. The 14 bp deletion/insertion polymorphism in the 3'-untranslated region (3'-UTR) was genotyped in 75 each of RSA and healthy couples, respectively, by PCR amplification of HLA-G exon 8. MedCalc, GraphPad Prism, Haploview, PLINK, and multifactor dimensionality reduction were used to analyze the data. RESULTS HLA-G screening revealed the presence of -762C/T, -725C/G, -716T/G, -689A/G, -486C/A, and -477C/G single nucleotide polymorphisms (SNPs) in the 5'-URR. At positions -762 and -477, the frequency of CC homozygotes was significantly higher in controls compared to the patients. The 14 bp deletion/insertion polymorphism in the 3'-UTR showed an association with RSA with the heterozygous genotype being significantly higher in RSA compared to controls. CONCLUSIONS The study indicates a protective role of the CC genotypes of the two HLA-G 5'-URR polymorphisms, -762C/T and -477C/G, against RSA. It also suggests that women with the 14 bp deletion/insertion genotype have a significantly higher risk of RSA.
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Affiliation(s)
- Binata Marik
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Khusru Nomani
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Nutan Agarwal
- Department of Obstetrics & Gynecology, AIIMS, New Delhi, India
| | - Vatsla Dadhwal
- Department of Obstetrics & Gynecology, AIIMS, New Delhi, India
| | - Arundhati Sharma
- Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, India
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14
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Campos-Mora M, Jacot W, Garcin G, Depondt ML, Constantinides M, Alexia C, Villalba M. NK cells in peripheral blood carry trogocytosed tumor antigens from solid cancer cells. Front Immunol 2023; 14:1199594. [PMID: 37593736 PMCID: PMC10427869 DOI: 10.3389/fimmu.2023.1199594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/10/2023] [Indexed: 08/19/2023] Open
Abstract
The innate immune lymphocyte lineage natural killer (NK) cell infiltrates tumor environment where it can recognize and eliminate tumor cells. NK cell tumor infiltration is linked to patient prognosis. However, it is unknown if some of these antitumor NK cells leave the tumor environment. In blood-borne cancers, NK cells that have interacted with leukemic cells are recognized by the co-expression of two CD45 isoforms (CD45RARO cells) and/or the plasma membrane presence of tumor antigens (Ag), which NK cells acquire by trogocytosis. We evaluated solid tumor Ag uptake by trogocytosis on NK cells by performing co-cultures in vitro. We analyzed NK population subsets by unsupervised dimensional reduction techniques in blood samples from breast tumor (BC) patients and healthy donors (HD). We confirmed that NK cells perform trogocytosis from solid cancer cells in vitro. The extent of trogocytosis depends on the target cell and the antigen, but not on the amount of Ag expressed by the target cell or the sensitivity to NK cell killing. We identified by FlowSOM (Self-Organizing Maps) several NK cell clusters differentially abundant between BC patients and HD, including anti-tumor NK subsets with phenotype CD45RARO+CD107a+. These analyses showed that bona-fide NK cells that have degranulated were increased in patients and, additionally, these NK cells exhibit trogocytosis of solid tumor Ag on their surface. However, the frequency of NK cells that have trogocytosed is very low and much lower than that found in hematological cancer patients, suggesting that the number of NK cells that exit the tumor environment is scarce. To our knowledge, this is the first report describing the presence of solid tumor markers on circulating NK subsets from breast tumor patients. This NK cell immune profiling could lead to generate novel strategies to complement established therapies for BC patients or to the use of peripheral blood NK cells in the theranostic of solid cancer patients after treatment.
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Affiliation(s)
| | - William Jacot
- Institut du Cancer de Montpellier (ICM) Val d’Aurelle, Montpellier University, INSERM U1194, Montpellier, France
| | | | | | | | | | - Martin Villalba
- IRMB, Univ Montpellier, INSERM, Montpellier, France
- IRMB, University of Montpellier, INSERM, CNRS, Montpellier, France
- Institut du Cancer Avignon-Provence Sainte Catherine, Avignon, France
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15
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Kilgour MK, Bastin DJ, Lee SH, Ardolino M, McComb S, Visram A. Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy. Front Immunol 2023; 14:1166038. [PMID: 37205115 PMCID: PMC10187144 DOI: 10.3389/fimmu.2023.1166038] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 04/12/2023] [Indexed: 05/21/2023] Open
Abstract
Advancements in chimeric antigen receptor engineered T-cell (CAR-T) therapy have revolutionized treatment for several cancer types over the past decade. Despite this success, obstacles including the high price tag, manufacturing complexity, and treatment-associated toxicities have limited the broad application of this therapy. Chimeric antigen receptor engineered natural killer cell (CAR-NK) therapy offers a potential opportunity for a simpler and more affordable "off-the-shelf" treatment, likely with fewer toxicities. Unlike CAR-T, CAR-NK therapies are still in early development, with few clinical trials yet reported. Given the challenges experienced through the development of CAR-T therapies, this review explores what lessons we can apply to build better CAR-NK therapies. In particular, we explore the importance of optimizing the immunochemical properties of the CAR construct, understanding factors leading to cell product persistence, enhancing trafficking of transferred cells to the tumor, ensuring the metabolic fitness of the transferred product, and strategies to avoid tumor escape through antigen loss. We also review trogocytosis, an important emerging challenge that likely equally applies to CAR-T and CAR-NK cells. Finally, we discuss how these limitations are already being addressed in CAR-NK therapies, and what future directions may be possible.
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Affiliation(s)
- Marisa K. Kilgour
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | | | - Seung-Hwan Lee
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
- Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada
| | - Michele Ardolino
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
- Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada
| | - Scott McComb
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
- Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Canada
| | - Alissa Visram
- Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada
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16
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MHC-dressing on dendritic cells: Boosting anti-tumor immunity via unconventional tumor antigen presentation. Semin Immunol 2023; 66:101710. [PMID: 36640616 DOI: 10.1016/j.smim.2023.101710] [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: 08/26/2022] [Revised: 12/21/2022] [Accepted: 01/07/2023] [Indexed: 01/15/2023]
Abstract
Dendritic cells are crucial for anti-tumor immune responses due to their ability to activate cytotoxic effector CD8+ T cells. Canonically, in anti-tumor immunity, dendritic cells activate CD8+ T cells in a process termed cross-presentation. Recent studies have demonstrated that another type of antigen presentation, MHC-dressing, also serves to activate CD8+ T cells against tumor cell-derived antigens. Understanding MHC-dressing's specific contributions to anti-tumor immunity can open up novel therapeutic avenues. In this review, we summarize the early studies that identified MHC-dressing as a relevant antigen presentation pathway before diving into a deeper discussion of the biology of MHC-dressing, focusing in particular on which dendritic cell subsets are most capable of performing MHC-dressing and how MHC-dressing compares to other forms of antigen presentation. We conclude by discussing the implications MHC-dressing has for anti-tumor immunity.
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17
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Bates M, Mohamed BM, Ward MP, Kelly TE, O'Connor R, Malone V, Brooks R, Brooks D, Selemidis S, Martin C, O'Toole S, O'Leary JJ. Circulating tumour cells: The Good, the Bad and the Ugly. Biochim Biophys Acta Rev Cancer 2023; 1878:188863. [PMID: 36796527 DOI: 10.1016/j.bbcan.2023.188863] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 01/06/2023] [Accepted: 01/21/2023] [Indexed: 02/17/2023]
Abstract
This review is an overview of the current knowledge regarding circulating tumour cells (CTCs), which are potentially the most lethal type of cancer cell, and may be a key component of the metastatic cascade. The clinical utility of CTCs (the "Good"), includes their diagnostic, prognostic, and therapeutic potential. Conversely, their complex biology (the "Bad"), including the existence of CD45+/EpCAM+ CTCs, adds insult to injury regarding their isolation and identification, which in turn hampers their clinical translation. CTCs are capable of forming microemboli composed of both non-discrete phenotypic populations such as mesenchymal CTCs and homotypic and heterotypic clusters which are poised to interact with other cells in the circulation, including immune cells and platelets, which may increase their malignant potential. These microemboli (the "Ugly") represent a prognostically important CTC subset, however, phenotypic EMT/MET gradients bring additional complexities to an already challenging situation.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Mark P Ward
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Tanya E Kelly
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Roisin O'Connor
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Victoria Malone
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Robert Brooks
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Doug Brooks
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Stavros Selemidis
- School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology, Bundoora, VIC 3083, Australia
| | - Cara Martin
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin 2, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
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18
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Meng M, Sun Y, Bai Y, Xu J, Sun J, Han L, Sun H, Han R. A polysaccharide from Pleurotus citrinopileatus mycelia enhances the immune response in cyclophosphamide-induced immunosuppressed mice via p62/Keap1/Nrf2 signal transduction pathway. Int J Biol Macromol 2023; 228:165-177. [PMID: 36543297 DOI: 10.1016/j.ijbiomac.2022.12.142] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/21/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The manuscript aimed to study the immunoregulatory activity and the mechanism of the polysaccharide (CMP) from Pleurotus citrinopileatus mycelia. The mice were divided into normal group, model group, different dosage of CMP (50, 100 and 200 mg/kg, respectively) groups and levamisole hydrochloride treated group. The results showed that, compared with the model group, CMP could significantly improve the auricle swelling rate, half hemolysis value and phagocytic index in mice. The indices of immune organs were raised, and tissue damage of spleen was relieved. Splenic Th1 cells were decreased, while Th2 cells were increased, furthermore the proliferation of splenic lymphocytes and the cytotoxicity of NK cells were increased. The levels of interleukin-12 (IL-12), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in spleen were decreased, while interleukin-4 (IL-4) and interleukin-10 (IL-10) were increased. In serum and spleen, the levels of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities were increased, while the level of malondialdehyde (MDA) was decreased. And the levels of Immunoglobulin were also increased. Western blot showed that CMP had immunoregulatory activity by activating Nrf2, Keap1, p62, HO-1, and NQO1 in the p62/Keap1/Nrf2 signaling pathway. The study proved that CMP could be used as a biological Immune regulating agent.
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Affiliation(s)
- Meng Meng
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Science and Engineering, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, China
| | - Ying Sun
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Science and Engineering, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, China
| | - Yuhe Bai
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Science and Engineering, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, China
| | - Jin Xu
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Science and Engineering, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, China
| | - Jingge Sun
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Science and Engineering, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, China
| | - Lirong Han
- Key Laboratory of Public Health Safety of Hebei Province, Ministry of Education & College of Public Health, Hebei University, Baoding 071002, China
| | - Huiqing Sun
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Science and Engineering, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, China
| | - Ran Han
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Science and Engineering, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, China.
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19
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Barbaro G, Inversetti A, Cristodoro M, Ticconi C, Scambia G, Di Simone N. HLA-G and Recurrent Pregnancy Loss. Int J Mol Sci 2023; 24:ijms24032557. [PMID: 36768880 PMCID: PMC9917226 DOI: 10.3390/ijms24032557] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/16/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Placentation is an immunological compromise where maternal immune system cells and trophoblastic cells interact to reach an equilibrium condition. Although the cross talk between the two systems is complex and not completely understood, Human Leukocyte Antigen G (HLA-G), expressed on trophoblastic cell surfaces, seems to be one of the main molecules involved in the modulation of both local and systemic maternal immune response. The prevalence of recurrent pregnancy loss (RPL), probably underestimated, is 5% of all women who achieve pregnancy, and about 40-60% percent of RPL cases are unexplained. There is an immunological analogy between allograft rejection and miscarriage, and the purpose of this review is to describe how the HLA-G pathway alterations are involved in disrupting the immunologic balance and in increasing the risk of recurrent pregnancy loss.
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Affiliation(s)
- Greta Barbaro
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), L. go A. Gemelli 8, 00168 Roma, Italy
| | - Annalisa Inversetti
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milano, Italy
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Martina Cristodoro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milano, Italy
| | - Carlo Ticconi
- Dipartimento di Scienze Chirurgiche, Ginecologia e Ostetricia, Università di Torvergata, 00168 Roma, Italy
| | - Giovanni Scambia
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), L. go A. Gemelli 8, 00168 Roma, Italy
- U.O.C. di Ginecologia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, L. go A. Gemelli 8, 00168 Rome, Italy
| | - Nicoletta Di Simone
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milano, Italy
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
- Correspondence:
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20
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Li Y, Basar R, Wang G, Liu E, Moyes JS, Li L, Kerbauy LN, Uprety N, Fathi M, Rezvan A, Banerjee PP, Muniz-Feliciano L, Laskowski TJ, Ensley E, Daher M, Shanley M, Mendt M, Acharya S, Liu B, Biederstädt A, Rafei H, Guo X, Melo Garcia L, Lin P, Ang S, Marin D, Chen K, Bover L, Champlin RE, Varadarajan N, Shpall EJ, Rezvani K. KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Nat Med 2022; 28:2133-2144. [PMID: 36175679 PMCID: PMC9942695 DOI: 10.1038/s41591-022-02003-x] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 08/09/2022] [Indexed: 01/21/2023]
Abstract
Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NKTROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a 'don't kill me' signal to NK cells upon engagement with their TROG+ siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
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Affiliation(s)
- Ye Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rafet Basar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guohui Wang
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Enli Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Judy S Moyes
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Li Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lucila N Kerbauy
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo, Sao Paulo, Brazil
- Department of Stem Cell Transplantation and Cellular Therapy, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Nadima Uprety
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mohsen Fathi
- Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA
| | - Ali Rezvan
- Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA
| | - Pinaki P Banerjee
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Luis Muniz-Feliciano
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tamara J Laskowski
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Emily Ensley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - May Daher
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mayra Shanley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mayela Mendt
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sunil Acharya
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bin Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexander Biederstädt
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Medicine III: Hematology and Oncology, Technical University of Munich, Munich, Germany
| | - Hind Rafei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xingliang Guo
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Luciana Melo Garcia
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paul Lin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sonny Ang
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David Marin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Laura Bover
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Richard E Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Navin Varadarajan
- Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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21
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Mattei F, Andreone S, Spadaro F, Noto F, Tinari A, Falchi M, Piconese S, Afferni C, Schiavoni G. Trogocytosis in innate immunity to cancer is an intimate relationship with unexpected outcomes. iScience 2022; 25:105110. [PMID: 36185368 PMCID: PMC9515589 DOI: 10.1016/j.isci.2022.105110] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/04/2022] [Accepted: 09/07/2022] [Indexed: 11/29/2022] Open
Abstract
Trogocytosis is a cellular process whereby a cell acquires a membrane fragment from a donor cell in a contact-dependent manner allowing for the transfer of surface proteins with functional integrity. It is involved in various biological processes, including cell-cell communication, immune regulation, and response to pathogens and cancer cells, with poorly defined molecular mechanisms. With the exception of eosinophils, trogocytosis has been reported in most immune cells and plays diverse roles in the modulation of anti-tumor immune responses. Here, we report that eosinophils acquire membrane fragments from tumor cells early after contact through the CD11b/CD18 integrin complex. We discuss the impact of trogocytosis in innate immune cells on cancer progression in the context of the evidence that eosinophils can engage in trogocytosis with tumor cells. We also discuss shared and cell-specific mechanisms underlying this process based on in silico modeling and provide a hypothetical molecular model for the stabilization of the immunological synapse operating in granulocytes and possibly other innate immune cells that enables trogocytosis.
Trogocytosis in innate immune cells can regulate immune responses to cancer Eosinophils engage in trogocytosis with tumor cells via CD11b/CD18 integrin complex CD11b/CD18 integrin, focal adhesion molecules and actin network enable trogocytosis
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Affiliation(s)
- Fabrizio Mattei
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Sara Andreone
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Francesca Spadaro
- Core Facilities, Microscopy Unit, Istituto Superiore di Sanità, Rome, Italy
| | - Francesco Noto
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Antonella Tinari
- Center for Gender Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Mario Falchi
- National HIV/AIDS Research Center (CNAIDS), Istituto Superiore di Sanità, Rome, Italy
| | - Silvia Piconese
- Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Italy
- Neuroimmunology Unit, IRCCS Fondazione Santa Lucia, Rome, Italy
- Laboratory Affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
| | - Claudia Afferni
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Giovanna Schiavoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
- Corresponding author
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22
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Duneton C, Winterberg PD, Ford ML. Activation and regulation of alloreactive T cell immunity in solid organ transplantation. Nat Rev Nephrol 2022; 18:663-676. [PMID: 35902775 PMCID: PMC9968399 DOI: 10.1038/s41581-022-00600-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2022] [Indexed: 01/18/2023]
Abstract
Transplantation is the only curative treatment for patients with kidney failure but it poses unique immunological challenges that must be overcome to prevent allograft rejection and ensure long-term graft survival. Alloreactive T cells are important contributors to graft rejection, and a clearer understanding of the mechanisms by which these cells recognize donor antigens - through direct, indirect or semi-direct pathways - will facilitate their therapeutic targeting. Post-T cell priming rejection responses can also be modified by targeting pathways that regulate T cell trafficking, survival cytokines or innate immune activation. Moreover, the quantity and quality of donor-reactive memory T cells crucially shape alloimmune responses. Of note, many fundamental concepts in transplant immunology have been derived from models of infection. However, the programmed differentiation of allograft-specific T cell responses is probably distinct from that of pathogen-elicited responses, owing to the dearth of pathogen-derived innate immune activation in the transplantation setting. Understanding the fundamental (and potentially unique) immunological pathways that lead to allograft rejection is therefore a prerequisite for the rational development of therapeutics that promote transplantation tolerance.
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Affiliation(s)
- Charlotte Duneton
- Paediatric Nephrology, Robert Debré Hospital, Paris, France
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Pamela D Winterberg
- Paediatric Nephrology, Emory University Department of Paediatrics and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Mandy L Ford
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
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23
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Harnessing natural killer cells for cancer immunotherapy: dispatching the first responders. Nat Rev Drug Discov 2022; 21:559-577. [PMID: 35314852 PMCID: PMC10019065 DOI: 10.1038/s41573-022-00413-7] [Citation(s) in RCA: 113] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2022] [Indexed: 02/07/2023]
Abstract
Natural killer (NK) cells have crucial roles in the innate immunosurveillance of cancer and viral infections. They are 'first responders' that can spontaneously recognize abnormal cells in the body, rapidly eliminate them through focused cytotoxicity mechanisms and potently produce pro-inflammatory cytokines and chemokines that recruit and activate other immune cells to initiate an adaptive response. From the initial discovery of the diverse cell surface receptors on NK cells to the characterization of regulatory events that control their function, our understanding of the basic biology of NK cells has improved dramatically in the past three decades. This advanced knowledge has revealed increased mechanistic complexity, which has opened the doors to the development of a plethora of exciting new therapeutics that can effectively manipulate and target NK cell functional responses, particularly in cancer patients. Here, we summarize the basic mechanisms that regulate NK cell biology, review a wide variety of drugs, cytokines and antibodies currently being developed and used to stimulate NK cell responses, and outline evolving NK cell adoptive transfer approaches to treat cancer.
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24
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Xie M, Li Y, Meng YZ, Xu P, Yang YG, Dong S, He J, Hu Z. Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation. Front Immunol 2022; 13:918550. [PMID: 35720413 PMCID: PMC9198966 DOI: 10.3389/fimmu.2022.918550] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/09/2022] [Indexed: 12/28/2022] Open
Abstract
Uterine natural killer (uNK) cells are an immune subset located in the uterus. uNK cells have distinct tissue-specific characteristics compared to their counterparts in peripheral blood and lymphoid organs. Based on their location and the pregnancy status of the host, uNK cells are classified as endometrial NK (eNK) cells or decidua NK (dNK) cells. uNK cells are important in protecting the host from pathogen invasion and contribute to a series of physiological processes that affect successful pregnancy, including uterine spiral artery remodeling, fetal development, and immunity tolerance. Abnormal alterations in uNK cell numbers and/or impaired function may cause pregnancy complications, such as recurrent miscarriage, preeclampsia, or even infertility. In this review, we introduce recent advances in human uNK cell research under normal physiological or pathological conditions, and summarize their unique influences on the process of pregnancy complications or uterine diseases. Finally, we propose the potential clinical use of uNK cells as a novel cellular immunotherapeutic approach for reproductive disorders.
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Affiliation(s)
- Min Xie
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
| | - Yan Li
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
| | - Yi-Zi Meng
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
| | - Peng Xu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China.,International Center of Future Science, Jilin University, Changchun, China
| | - Shuai Dong
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
| | - Jin He
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
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25
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Delgado-Gonzalez A, Huang YW, Porpiglia E, Donoso K, Gonzalez VD, Fantl WJ. Measuring trogocytosis between ovarian tumor and natural killer cells. STAR Protoc 2022; 3:101425. [PMID: 35693208 PMCID: PMC9185020 DOI: 10.1016/j.xpro.2022.101425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Trogocytosis is an active transport mechanism by which one cell extracts a plasma membrane fragment with embedded molecules from an adjacent cell in a contact-dependent process leading to the acquisition of a new function. Our protocol, which has general applicability, consolidates and optimizes existing protocols while highlighting key experimental variables to demonstrate that natural killer (NK) cells acquire the tetraspanin CD9 by trogocytosis from ovarian tumor cells. For complete details on the use and execution of this protocol, please refer to Gonzalez et al. (2021).
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Affiliation(s)
- Antonio Delgado-Gonzalez
- Deparment of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ying-Wen Huang
- Deparment of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ermelinda Porpiglia
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
| | - Kenyi Donoso
- Deparment of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Veronica D. Gonzalez
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wendy J. Fantl
- Deparment of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA
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26
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Xu X, Zhou Y, Fu B, Wei H. Uterine NK cell functions at maternal-fetal interface. Biol Reprod 2022; 107:327-338. [PMID: 35551350 DOI: 10.1093/biolre/ioac094] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 04/21/2022] [Accepted: 04/29/2022] [Indexed: 11/14/2022] Open
Abstract
During pregnancy, maternal decidual tissue interacts with fetal trophoblasts. They constitute the maternal-fetal interface responsible for supplying nutrition to the fetus. Uterine natural killer (uNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy and play critical roles throughout pregnancy. This review provides current knowledge about the functions of uNK cells. uNK cells have been shown to facilitate remodeling of the spiral artery, control the invasion of extravillous trophoblast (EVT) cells, contribute to the induction and maintenance of immune tolerance, protect against pathogen infection, and promote fetal development. Pregnancy-trained memory of uNK cells improves subsequent pregnancy outcomes. In addition, this review describes the distinct functions of three uNK cell subsets: CD27-CD11b-, CD27+ and CD27-CD11b+ uNK cells.
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Affiliation(s)
- Xiuxiu Xu
- Institute of Gerontology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China.,Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China
| | - Yonggang Zhou
- Institute of Gerontology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China.,Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China
| | - Binqing Fu
- Institute of Gerontology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China.,Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China
| | - Haiming Wei
- Institute of Gerontology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China.,Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China
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27
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Devvanshi H, Kachhwaha R, Manhswita A, Bhatnagar S, Kshetrapal P. Immunological Changes in Pregnancy and Prospects of Therapeutic Pla-Xosomes in Adverse Pregnancy Outcomes. Front Pharmacol 2022; 13:895254. [PMID: 35517798 PMCID: PMC9065684 DOI: 10.3389/fphar.2022.895254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
Stringent balance of the immune system is a key regulatory factor in defining successful implantation, fetal development, and timely parturition. Interference in these primary regulatory mechanisms, either at adolescence or prenatal state led to adverse pregnancy outcomes. Fertility restoration with the help of injectable gonadotrophins/progesterone, ovulation-inducing drugs, immunomodulatory drugs (corticosteroids), and reproductive surgeries provides inadequate responses, which manifest its own side effects. The development of a potential diagnostic biomarker and an effectual treatment for adverse pregnancy outcomes is a prerequisite to maternal and child health. Parent cell originated bi-layered-intraluminal nano-vesicles (30-150 nm) also known as exosomes are detected in all types of bodily fluids like blood, saliva, breast milk, urine, etc. Exosomes being the most biological residual structures with the least cytotoxicity are loaded with cargo in the form of RNAs (miRNAs), proteins (cytokines), hormones (estrogen, progesterone, etc.), cDNAs, and metabolites making them chief molecules of cell-cell communication. Their keen involvement in the regulation of biological processes has portrayed them as the power shots of cues to understand the disease's pathophysiology and progression. Recent studies have demonstrated the role of immunexosomes (immunomodulating exosomes) in maintaining unwavering immune homeostasis between the mother and developing fetus for a healthy pregnancy. Moreover, the concentration and size of the exosomes are extensively studied in adverse pregnancies like preeclampsia, gestational diabetes mellitus (GDM), and preterm premature rupture of membrane (pPROMs) as an early diagnostic marker, thus giving in-depth information about their pathophysiology. Exosomes have also been engineered physically as well as genetically to enhance their encapsulation efficiency and specificity in therapy for cancer and adverse pregnancies. Successful bench to bedside discoveries and interventions in cancer has motivated developmental biologists to investigate the role of immunexosomes and their active components. Our review summarizes the pre-clinical studies for the use of these power-shots as therapeutic agents. We envisage that these studies will pave the path for the use of immunexosomes in clinical settings for reproductive problems that arise due to immune perturbance in homeostasis either at adolescence or prenatal state.
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Affiliation(s)
- Himadri Devvanshi
- Maternal and Child Health, Translational Health Science and Technology Institute, Faridabad, India
| | - Rohit Kachhwaha
- Maternal and Child Health, Translational Health Science and Technology Institute, Faridabad, India
| | - Anima Manhswita
- School of Agriculture and Food Science, The University of Queensland, Brisbane, QLD, Australia
| | - Shinjini Bhatnagar
- Maternal and Child Health, Translational Health Science and Technology Institute, Faridabad, India
| | - Pallavi Kshetrapal
- Maternal and Child Health, Translational Health Science and Technology Institute, Faridabad, India
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28
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Hasim MS, Marotel M, Hodgins JJ, Vulpis E, Makinson OJ, Asif S, Shih HY, Scheer AK, MacMillan O, Alonso FG, Burke KP, Cook DP, Li R, Petrucci MT, Santoni A, Fallon PG, Sharpe AH, Sciumè G, Veillette A, Zingoni A, Gray DA, McCurdy A, Ardolino M. When killers become thieves: Trogocytosed PD-1 inhibits NK cells in cancer. SCIENCE ADVANCES 2022; 8:eabj3286. [PMID: 35417234 PMCID: PMC9007500 DOI: 10.1126/sciadv.abj3286] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 02/23/2022] [Indexed: 05/12/2023]
Abstract
Trogocytosis modulates immune responses, with still unclear underlying molecular mechanisms. Using leukemia mouse models, we found that lymphocytes perform trogocytosis at high rates with tumor cells. While performing trogocytosis, both Natural Killer (NK) and CD8+ T cells acquire the checkpoint receptor PD-1 from leukemia cells. In vitro and in vivo investigation revealed that PD-1 on the surface of NK cells, rather than being endogenously expressed, was derived entirely from leukemia cells in a SLAM receptor-dependent fashion. PD-1 acquired via trogocytosis actively suppressed NK cell antitumor immunity. PD-1 trogocytosis was corroborated in patients with clonal plasma cell disorders, where NK cells that stained for PD-1 also stained for tumor cell markers. Our results, in addition to shedding light on a previously unappreciated mechanism underlying the presence of PD-1 on NK and cytotoxic T cells, reveal the immunoregulatory effect of membrane transfer occurring when immune cells contact tumor cells.
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Affiliation(s)
- Mohamed S. Hasim
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- CI3, University of Ottawa, Ottawa, ON, Canada
| | - Marie Marotel
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- CI3, University of Ottawa, Ottawa, ON, Canada
| | - Jonathan J. Hodgins
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- CI3, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Elisabetta Vulpis
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci-Bolognetti, Rome, Italy
| | - Olivia J. Makinson
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- CI3, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Sara Asif
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- CI3, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Han-Yun Shih
- Neuro-Immune Regulome Unit, National Eye Institute, NIH, Bethesda, MD, USA
| | - Amit K. Scheer
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Olivia MacMillan
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- CI3, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Felipe G. Alonso
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Kelly P. Burke
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - David P. Cook
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Rui Li
- Department of Medicine, McGill University, Montréal, QC, Canada
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada
| | - Maria Teresa Petrucci
- Department of Cellular Biotechnology and Hematology, “Sapienza” University of Rome, Rome, Italy
| | - Angela Santoni
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci-Bolognetti, Rome, Italy
- IRCCS Neuromed, Pozzilli, Italy
| | - Padraic G. Fallon
- School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Arlene H. Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
| | - Giuseppe Sciumè
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci-Bolognetti, Rome, Italy
| | - André Veillette
- Department of Medicine, McGill University, Montréal, QC, Canada
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC, Canada
- Department of Medicine, University of Montréal, Montréal, QC, Canada
| | - Alessandra Zingoni
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci-Bolognetti, Rome, Italy
| | - Douglas A. Gray
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Arleigh McCurdy
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Michele Ardolino
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- CI3, University of Ottawa, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
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29
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Jasinski-Bergner S, Eckstein M, Taubert H, Wach S, Fiebig C, Strick R, Hartmann A, Seliger B. The Human Leukocyte Antigen G as an Immune Escape Mechanism and Novel Therapeutic Target in Urological Tumors. Front Immunol 2022; 13:811200. [PMID: 35185904 PMCID: PMC8855320 DOI: 10.3389/fimmu.2022.811200] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/13/2022] [Indexed: 02/06/2023] Open
Abstract
The non-classical human leukocyte antigen G (HLA-G) is a potent regulatory protein involved in the induction of immunological tolerance. This is based on the binding of membrane-bound as well as soluble HLA-G to inhibitory receptors expressed on various immune effector cells, in particular NK cells and T cells, leading to their attenuated functions. Despite its restricted expression on immune-privileged tissues under physiological conditions, HLA-G expression has been frequently detected in solid and hematopoietic malignancies including urological cancers, such as renal cell and urothelial bladder carcinoma and has been associated with progression of urological cancers and poor outcome of patients: HLA-G expression protects tumor cells from anti-tumor immunity upon interaction with its inhibitory receptors by modulating both the phenotype and function of immune cells leading to immune evasion. This review will discuss the expression, regulation, functional and clinical relevance of HLA-G expression in urological tumors as well as its use as a putative biomarker and/or potential therapeutic target for the treatment of renal cell carcinoma as well as urothelial bladder cancer.
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Affiliation(s)
- Simon Jasinski-Bergner
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Markus Eckstein
- Institute of Pathology, Universitätsklinikum Erlangen, Erlangen, Germany.,Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany
| | - Helge Taubert
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany.,Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Sven Wach
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany.,Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Fiebig
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany.,Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Reiner Strick
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany.,Laboratory of Molecular Medicine, Department of Gynecology & Obstetrics, University Hospital Erlangen, Friedrich Alexander University (FAU), Erlangen-Nürnberg, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, Universitätsklinikum Erlangen, Erlangen, Germany.,Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), Erlangen, Germany
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.,Main Department of GMP Cell and Gene Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
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30
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HLA-G and Other Immune Checkpoint Molecules as Targets for Novel Combined Immunotherapies. Int J Mol Sci 2022; 23:ijms23062925. [PMID: 35328349 PMCID: PMC8948858 DOI: 10.3390/ijms23062925] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 12/14/2022] Open
Abstract
HLA-G is an HLA-class Ib molecule that is involved in the establishment of tolerance at the maternal/fetal interface during pregnancy. The expression of HLA-G is highly restricted in adults, but the de novo expression of this molecule may be observed in different hematological and solid tumors and is related to cancer progression. Indeed, tumor cells expressing high levels of HLA-G are able to suppress anti-tumor responses, thus escaping from the control of the immune system. HLA-G has been proposed as an immune checkpoint (IC) molecule due to its crucial role in tumor progression, immune escape, and metastatic spread. We here review data available in the literature in which the interaction between HLA-G and other IC molecules is reported, in particular PD-1, CTLA-4, and TIM-3, but also IDO and TIGIT. Clinical trials using monoclonal antibodies against HLA-G and other IC are currently ongoing with cancer patients where antibodies and inhibitors of PD-1 and CTLA-4 showed encouraging results. With this background, we may envisage that combined therapies using antibodies targeting HLA-G and another IC may be successful for clinical purposes. Indeed, such immunotherapeutic protocols may achieve a better rescue of effective anti-tumor immune response, thus improving the clinical outcome of patients.
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31
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Martín-Villa JM, Vaquero-Yuste C, Molina-Alejandre M, Juarez I, Suárez-Trujillo F, López-Nares A, Palacio‐Gruber J, Barrera-Gutiérrez L, Fernández-Cruz E, Rodríguez-Sainz C, Arnaiz-Villena A. HLA-G: Too Much or Too Little? Role in Cancer and Autoimmune Disease. Front Immunol 2022; 13:796054. [PMID: 35154112 PMCID: PMC8829012 DOI: 10.3389/fimmu.2022.796054] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
HLA-G is a non-classical HLA class I molecule with immunomodulatory properties. It was initially described at the maternal-fetal interface, and it was later found that this molecule was constitutively expressed on certain immuneprivileged tissues, such as cornea, endothelial and erythroid precursors, and thymus. The immunosuppressive effect of HLA-G is exerted through the interaction with its cognate receptors, expressed on immunocompetent cells, like ILT2, expressed on NK, B, T cells and APCs; ILT4, on APCs; KIR, found on the surface of NK cells; and finally, the co-receptor CD8. Because of these immunomodulatory functions, HLA-G has been involved in several processes, amongst which organ transplantation, viral infections, cancer progression, and autoimmunity. HLA-G neo-expression on tumors has been recently described in several types of malignancies. In fact, tumor progression is tightly linked to the presence of the molecule, as it exerts its tolerogenic function, inhibiting the cells of the immune system and favoring tumor escape. Several polymorphisms in the 3'UTR region condition changes in HLA-G expression (14bp and +3142C/G, among others), which have been associated with both the development and outcome of patients with different tumor types. Also, in recent years, several studies have shown that HLA-G plays an important role in the control of autoimmune diseases. The ability of HLA-G to limit the progression of these diseases has been confirmed and, in fact, levels of the molecule and several of its polymorphisms have been associated with increased susceptibility to the development of autoimmune diseases, as well as increased disease severity. Thus, modulating HLA-G expression in target tissues of oncology patients or patients with autoimmune diseases may be potential therapeutic approaches to treat these pathological conditions.
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Affiliation(s)
- José Manuel Martín-Villa
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Christian Vaquero-Yuste
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Marta Molina-Alejandre
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Ignacio Juarez
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Fabio Suárez-Trujillo
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Adrián López-Nares
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - José Palacio‐Gruber
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Luis Barrera-Gutiérrez
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Eduardo Fernández-Cruz
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Servicio de Inmunología, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Carmen Rodríguez-Sainz
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Servicio de Inmunología, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Antonio Arnaiz-Villena
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
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32
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Sun YX, Feng Q, Wang SW, Li X, Sheng Z, Peng J. HLA-G-ILT2 interaction contributes to suppression of bone marrow B cell proliferation in acquired aplastic anemia. Ann Hematol 2022; 101:739-748. [PMID: 35041051 DOI: 10.1007/s00277-022-04757-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 01/09/2022] [Indexed: 12/17/2022]
Abstract
Acquired aplastic anemia (AA) is an autoimmune disease characterized by hematopoietic stem and progenitor cell destruction in bone marrow. The non-classic human leukocyte class I antigen (HLA-) G interacts with multiple cell subsets, such as T cells and B cells. HLA-G exerts powerful immune suppression by binding with its receptors, immunoglobulin-like transcripts (ILTs). Here, we compared 46 AA patients and 28 healthy controls. Soluble HLA-G levels in bone marrow supernatants from AA patients were higher than controls. The proportion of bone marrow B cells was decreased and the ILT2-expressing cells among CD19+ cells were increased in AA patients. In addition, the percentage of mature B cells among marrow B cells was increased in AA patient, while the percentage of pro-B plus pre-B cells was decreased. More immature B cells and pro-B plus pre-B cells expressed ILT2 in AA patients than in controls, while mature B cells expressing ILT2 did not differ significantly. Functional studies demonstrated that high-level soluble HLA-G inhibited bone marrow B cell proliferation by interacting with ILT2 in AA, and was blocked by anti-HLA-G and anti-ILT2 monoclonal antibodies. Together, these results suggest that the abnormal decrease of pro-B plus pre-B cells in AA patients was related to the enhanced suppression by the excess HLA-G and ILT2 proteins. Therapeutic blockade of the HLA-G-ILT2 interaction may help to normalize bone marrow B cell proliferation.
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Affiliation(s)
- Yuan-Xin Sun
- Department of Hemodialysis, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qi Feng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shu-Wen Wang
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xin Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zi Sheng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. .,School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. .,State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
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33
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Negrini S, Contini P, Murdaca G, Puppo F. HLA-G in Allergy: Does It Play an Immunoregulatory Role? Front Immunol 2022; 12:789684. [PMID: 35082780 PMCID: PMC8784385 DOI: 10.3389/fimmu.2021.789684] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/15/2021] [Indexed: 11/29/2022] Open
Abstract
Allergy is an inflammatory process determined by a cascade of immune events characterized by T-helper 2 lymphocytes polarization leading to interleukin-4 upregulation, IgE secretion, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, are known to play a key immunoregulatory role and their involvement in allergic diseases is supported by increasing literature data. HLA-G expression and secretion is specifically induced in peripheral blood mononuclear cells of allergic patients after in vitro incubation with the causal allergen. Elevated levels of soluble HLA-G molecules are detected in serum of patients with allergic rhinitis correlating with allergen-specific IgE levels, clinical severity, drug consumption and response to allergen-specific immunotherapy. HLA-G genetic polymorphisms confer susceptibility to allergic asthma development and high levels of soluble HLA-G molecules are found in plasma and bronchoalveolar lavage fluid of patients with allergic asthma correlating with allergen-specific IgE levels. Interestingly, allergic pregnant women have lower plasma sHLA-G levels than non-allergic women during the 3rd trimester of pregnancy and at delivery. Finally, in allergic patients with atopic dermatitis HLA-G molecules are expressed by T cells, monocytes-macrophages and Langerhans cells infiltrating the dermis. Although at present is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are specifically expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation.
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Affiliation(s)
| | | | | | - Francesco Puppo
- Department of Internal Medicine, University of Genoa, Genoa, Italy
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34
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The HLA-G Immune Checkpoint Plays a Pivotal Role in the Regulation of Immune Response in Autoimmune Diseases. Int J Mol Sci 2021; 22:ijms222413348. [PMID: 34948145 PMCID: PMC8706866 DOI: 10.3390/ijms222413348] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022] Open
Abstract
The human G-leukocyte antigen (HLA-G) molecule is a non-classical major histocompatibility complex (MHC) class I molecule. The pertinence of HLA-G has been investigated in numerous studies which have sought to elucidate the relevance of HLA-G in pathologic conditions, such as autoimmune diseases, cancers, and hematologic malignancies. One of the main goals of the current research on HLA-G is to use this molecule in clinical practice, either in diagnostics or as a therapeutic target. Since HLA-G antigens are currently considered as immunomodulatory molecules that are involved in reducing inflammatory and immune responses, in this review, we decided to focus on this group of antigens as potential determinants of progression in autoimmune diseases. This article highlights what we consider as recent pivotal findings on the immunomodulatory function of HLA-G, not only to establish the role of HLA-G in the human body, but also to explain how these proteins mediate the immune response.
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35
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Hosseini M, Habibi Z, Hosseini N, Abdoli S, Rezaei N. Preclinical studies of chimeric antigen receptor-modified natural killer cells in cancer immunotherapy: a review. Expert Opin Biol Ther 2021; 22:349-366. [PMID: 34541989 DOI: 10.1080/14712598.2021.1983539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION As one of the most efficacious methods of cancer immunotherapy, chimeric antigen receptor-modified immune cells have recently drawn enormous attention. After the great success achieved with CAR-T-cells in cancer treatment both in preclinical setting and in the clinic, other types of immune cells, including natural killer (NK)-cells and macrophages, have been evaluated for their anti-cancer effects along with their potential superiority against CAR-T-cells, especially in terms of safety. First introduced by Tran et al. almost 26 years ago, CAR-NK-cells are now being considered as efficient immunotherapeutic modalities in various types of cancers, not only in preclinical setting but also in numerous phase I and II clinical studies. AREAS COVERED In this review, we aim to provide a comprehensive survey of the preclinical studies on CAR-NK-cells' development, with an evolutional approach on CAR structures and their associated signaling moieties. Current NK-cell sources and modes of gene transfer are also reviewed. EXPERT OPINION CAR-NK-cells have appeared as safe and effective immunotherapeutic tools in preclinical settings; however, designing CAR structures with an eye on their specific biology, along with choosing the optimal cell source and gene transfer method require further investigation to support clinical studies.
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Affiliation(s)
- Mina Hosseini
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Habibi
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Narges Hosseini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sina Abdoli
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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36
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The Role and Clinical Interest of Extracellular Vesicles in Pregnancy and Ovarian Cancer. Biomedicines 2021; 9:biomedicines9091257. [PMID: 34572444 PMCID: PMC8464910 DOI: 10.3390/biomedicines9091257] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/14/2021] [Accepted: 09/14/2021] [Indexed: 12/21/2022] Open
Abstract
Ovarian cancer and pregnancy are two states in which the host immune system is exposed to novel antigens. Indeed, both the tumor and placenta must invade tissues, remodel vasculature to establish a robust blood supply, and evade detection by the immune system. Interestingly, tumor and placenta tissue use similar mechanisms to induce these necessary changes. One mediator is emerging as a key player in invasion, vascular remodeling, and immune evasion: extracellular vesicles (EVs). Many studies have identified EVs as a key mediator of cell-to-cell communication. Specifically, the cargo carried by EVs, which includes proteins, nucleic acids, and lipids, can interact with cells to induce changes in the target cell ranging from gene expression to migration and metabolism. EVs can promote cell division and tissue invasion, immunosuppression, and angiogenesis which are essential for both cancer and pregnancy. In this review, we examine the role of EVs in ovarian cancer metastasis, chemoresistance, and immune modulation. We then focus on the role of EVs in pregnancy with special attention on the vascular remodeling and regulation of the maternal immune system. Lastly, we discuss the clinical utility of EVs as markers and therapeutics for ovarian cancer and pre-eclampsia.
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37
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Gonzalez VD, Huang YW, Delgado-Gonzalez A, Chen SY, Donoso K, Sachs K, Gentles AJ, Allard GM, Kolahi KS, Howitt BE, Porpiglia E, Fantl WJ. High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment. Cell Rep 2021; 36:109632. [PMID: 34469729 PMCID: PMC8546503 DOI: 10.1016/j.celrep.2021.109632] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 05/12/2021] [Accepted: 08/06/2021] [Indexed: 12/30/2022] Open
Abstract
Tubo-ovarian high-grade serous carcinoma (HGSC) is unresponsive to immune checkpoint blockade despite significant frequencies of exhausted T cells. Here we apply mass cytometry and uncover decidual-like natural killer (dl-NK) cell subpopulations (CD56+CD9+CXCR3+KIR+CD3-CD16-) in newly diagnosed HGSC samples that correlate with both tumor and transitioning epithelial-mesenchymal cell abundance. We show different combinatorial expression patterns of ligands for activating and inhibitory NK receptors within three HGSC tumor compartments: epithelial (E), transitioning epithelial-mesenchymal (EV), and mesenchymal (vimentin expressing [V]), with a more inhibitory ligand phenotype in V cells. In cocultures, NK-92 natural killer cells acquire CD9 from HGSC tumor cells by trogocytosis, resulting in reduced anti-tumor cytokine production and cytotoxicity. Cytotoxicity in these cocultures is restored with a CD9-blocking antibody or CD9 CRISPR knockout, thereby identifying mechanisms of immune suppression in HGSC. CD9 is widely expressed in HGSC tumors and so represents an important new therapeutic target with immediate relevance for NK immunotherapy.
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MESH Headings
- Antineoplastic Agents/pharmacology
- Carboplatin/pharmacology
- Cell Line, Tumor
- Coculture Techniques
- Cytokines/metabolism
- Cytotoxicity, Immunologic
- Female
- Humans
- Immune Tolerance/drug effects
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Lymphocytes, Tumor-Infiltrating/drug effects
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Neoplasms, Cystic, Mucinous, and Serous/drug therapy
- Neoplasms, Cystic, Mucinous, and Serous/immunology
- Neoplasms, Cystic, Mucinous, and Serous/metabolism
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Ovarian Neoplasms/drug therapy
- Ovarian Neoplasms/immunology
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- Phenotype
- Receptors, Natural Killer Cell/metabolism
- Tetraspanin 29/metabolism
- Trogocytosis
- Tumor Escape/drug effects
- Tumor Microenvironment/immunology
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Affiliation(s)
- Veronica D Gonzalez
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ying-Wen Huang
- Department of Urology Stanford University School of Medicine, Stanford, CA 94305, USA
| | | | - Shih-Yu Chen
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Kenyi Donoso
- Department of Urology Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Karen Sachs
- Next Generation Analytics, Palo Alto, CA 94301, USA
| | - Andrew J Gentles
- Department of Medicine (Quantitative Sciences Unit, Biomedical Informatics) Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Grace M Allard
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Kevin S Kolahi
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Brooke E Howitt
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ermelinda Porpiglia
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wendy J Fantl
- Department of Urology Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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38
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Lu T, Ma R, Li Z, Mansour AG, Teng KY, Chen L, Zhang J, Barr T, Caligiuri MA, Yu J. Hijacking TYRO3 from Tumor Cells via Trogocytosis Enhances NK-Cell Effector Functions and Proliferation. Cancer Immunol Res 2021; 9:1229-1241. [PMID: 34326137 DOI: 10.1158/2326-6066.cir-20-1014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/15/2021] [Accepted: 07/22/2021] [Indexed: 11/16/2022]
Abstract
Trogocytosis is a fast, cell-cell contact-dependent uptake of membrane patches and associated molecules by one cell from another. Here, we report our investigation of trogocytosis of TYRO3, a cell membrane protein, from tumor target cells to natural killer (NK) cells and the associated functional consequences for NK cells. We found that although NK cells did not express endogenous TYRO3 on the cell surface, activated NK cells rapidly acquired TYRO3 from tumor cells via trogocytosis in vitro and in vivo. NK cells that acquired TYRO3, which we termed TYRO3+ NK cells, had significantly enhanced cytotoxicity and IFNγ production as well as higher expression of some activated surface markers compared with TYRO3- NK cells. Furthermore, the activation status of NK cells and TYRO3 expression levels on donor cells, either endogenous or ectopic, positively correlated with trogocytosis levels. When the antigen-presenting cell (APC) K562 leukemia cell line, a feeder cell line to expand NK cells, overexpressed TYRO3, TYRO3 was transferred to NK cells via trogocytosis, which improved NK-cell proliferation ex vivo. This provides a strategy to manufacture NK cells or their engineered counterparts, such as chimeric antigen receptor NK cells, for the treatment of cancer or infectious diseases.
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Affiliation(s)
- Ting Lu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California
| | - Rui Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California
| | - Zhenlong Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California
| | - Anthony G Mansour
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California
| | - Kun-Yu Teng
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California
| | - Li Chen
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California
| | - Jianying Zhang
- Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, California
| | - Tasha Barr
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California. .,Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Los Angeles, California.,Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California.,City of Hope Comprehensive Cancer Center, Los Angeles, California
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California. .,Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Los Angeles, California.,Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California.,City of Hope Comprehensive Cancer Center, Los Angeles, California
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Miyake K, Karasuyama H. The Role of Trogocytosis in the Modulation of Immune Cell Functions. Cells 2021; 10:cells10051255. [PMID: 34069602 PMCID: PMC8161413 DOI: 10.3390/cells10051255] [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: 04/30/2021] [Revised: 05/15/2021] [Accepted: 05/17/2021] [Indexed: 12/16/2022] Open
Abstract
Trogocytosis is an active process, in which one cell extracts the cell fragment from another cell, leading to the transfer of cell surface molecules, together with membrane fragments. Recent reports have revealed that trogocytosis can modulate various biological responses, including adaptive and innate immune responses and homeostatic responses. Trogocytosis is evolutionally conserved from protozoan parasites to eukaryotic cells. In some cases, trogocytosis results in cell death, which is utilized as a mechanism for antibody-dependent cytotoxicity (ADCC). In other cases, trogocytosis-mediated intercellular protein transfer leads to both the acquisition of novel functions in recipient cells and the loss of cellular functions in donor cells. Trogocytosis in immune cells is typically mediated by receptor–ligand interactions, including TCR–MHC interactions and Fcγ receptor-antibody-bound molecule interactions. Additionally, trogocytosis mediates the transfer of MHC molecules to various immune and non-immune cells, which confers antigen-presenting activity on non-professional antigen-presenting cells. In this review, we summarize the recent advances in our understanding of the role of trogocytosis in immune modulation.
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Cwykiel J, Madajka-Niemeyer M, Siemionow M. Development of Donor Recipient Chimeric Cells of bone marrow origin as a novel approach for tolerance induction in transplantation. Stem Cell Investig 2021; 8:8. [PMID: 33969113 DOI: 10.21037/sci-2020-044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Background Cell therapies and chimerism-based strategies are currently the most successful approach for tolerance induction in transplantation. This study aimed to establish and characterize novel Donor Recipient Chimeric Ccell (DRCC) therapy of bone marrow (BM) origin presenting donor-recipient phenotype to support tolerance induction. Methods Ex vivo fusions of fully MHC-mismatched BM cells from ACI (RT1a) and Lewis (RT1l) rats were performed using polyethylene-glycol (PEG). The creation of rat DRCC was tested by flow cytometry (FC), confocal microscopy and PCR. FC characterized DRCC's phenotype (CD3, CD4, CD8, CD45, CD90, CD11b/c, CD45RA, OX-82, or CD4/CD25) and apoptosis, while mixed lymphocyte reaction assessed DRCC's immunogenicity and colony forming unit assay tested DRCC's differentiation and proliferation. DRCC's polyploidy was evaluated using Hoechst33342 staining and COMET assay tested genotoxicity of fusion procedure. ELISA analyzed the secretion of IL-2, IL-4, IL-10, TGFß1, IFNγ and TNFα by DRCC at day 1, 5 and 14 post-fusion. The DRCC's phenotype after long-term culturing was assessed by reverse-transcription PCR. Results The chimeric state of DRCC was confirmed. Fusion did not change the expression of hematopoietic markers compared to BM controls. Although an increased number of early and late apoptotic (Annexin V+/Sytox blue- and Annexin V+/Sytox blue+, respectively) DRCC was detected at 24h post-fusion, the number significantly decreased at day 5 (38.4%±3.1% and 22.6%±2.5%, vs. 28.3%±2.5% and 13.9%±2.6%, respectively, P<0.05). DRCC presented decreased immunogenicity, increased expression of IL-10 and TGFβ1 and proliferative potential comparable to BM controls. The average percentage of tetraploid DRCC was 3.1%±0.2% compared to 0.96%±0.1% in BM controls. The lack of damage to the DRCC's DNA content supported the DRCC's safety. In culture, DRCC maintained proliferation for up to 28 days while preserving hematopoietic profile. Conclusions This study confirmed feasibility of DRCC creation via ex vivo PEG mediated fusion. The created DRCC revealed pro-tolerogenic properties indicating potential immunomodulatory effect of DRCC therapy when applied in vivo to support tolerance induction in solid organ and vascularized composite allograft transplantation.
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Affiliation(s)
- Joanna Cwykiel
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Maria Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland
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Rouas-Freiss N, Moreau P, LeMaoult J, Papp B, Tronik-Le Roux D, Carosella ED. Role of the HLA-G immune checkpoint molecule in pregnancy. Hum Immunol 2021; 82:353-361. [PMID: 33745758 DOI: 10.1016/j.humimm.2021.01.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/22/2020] [Accepted: 01/05/2021] [Indexed: 12/21/2022]
Abstract
The non-classical HLA class I molecule HLA-G is expressed in trophoblasts where it contributes to maternal-fetal tolerance. HLA-G has been implicated in the control of trophoblast invasion, uterine vascular remodeling, and maintenance of a local immunosuppressive state. Understanding HLA-G biology at the maternal-fetal interface is therefore a critical issue in reproduction. In this regard, we review here: (i) the effects of HLA-G on decidual leucocytes and stromal cells, (ii) the contribution of trogocytosis in HLA-G expression on decidual cells, (iii) its interaction with the ILT2, ILT4 and KIR2DL4 receptors, (iv) the link between HLA-G polymorphism and pregnancy disorders, and (v) the expression of newly-described HLA-G isoforms at the maternal-fetal interface.
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Affiliation(s)
- Nathalie Rouas-Freiss
- CEA, DRF-Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France; U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Philippe Moreau
- CEA, DRF-Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France; U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Joel LeMaoult
- CEA, DRF-Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France; U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Bela Papp
- CEA, DRF-Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France; U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Diana Tronik-Le Roux
- CEA, DRF-Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France; U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Edgardo D Carosella
- CEA, DRF-Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France; U976 HIPI Unit, IRSL, Université Paris, Paris, France.
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Anna F, Bole-Richard E, LeMaoult J, Escande M, Lecomte M, Certoux JM, Souque P, Garnache F, Adotevi O, Langlade-Demoyen P, Loustau M, Caumartin J. First immunotherapeutic CAR-T cells against the immune checkpoint protein HLA-G. J Immunother Cancer 2021; 9:e001998. [PMID: 33737343 PMCID: PMC7978334 DOI: 10.1136/jitc-2020-001998] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND CAR-T cells immunotherapy is a breakthrough in the treatment of hematological malignancies such as acute lymphoblastic leukemia (ALL) and B-cell malignancies. However, CAR-T therapies face major hurdles such as the lack of tumor-specific antigen (TSA), and immunosuppressive tumor microenvironment sometimes caused by the tumorous expression of immune checkpoints (ICPs) such as HLA-G. Indeed, HLA-G is remarkable because it is both a potent ICP and a TSA. HLA-G tumor expression causes immune escape by impairing innate and adaptive immune responses and by inducing a suppressive microenvironment. Yet, to date, no immunotherapy targets it. METHODS We have developed two anti-HLA-G third-generation CARs based on new anti-HLA-G monoclonal antibodies. RESULTS Anti-HLA-G CAR-T cells were specific for immunosuppressive HLA-G isoforms. HLA-G-activated CAR-T cells polarized toward T helper 1, and became cytotoxic against HLA-G+ tumor cells. In vivo, anti-HLA-G CAR-T cells were able to control and eliminate HLA-G+ tumor cells. The interaction of tumor-HLA-G with interleukin (IL)T2-expressing T cells is known to result in effector T cell functional inhibition, but anti-HLA-G CAR-T cells were insensitive to this inhibition and still exerted their function even when expressing ILT2. Lastly, we show that anti-HLA-G CAR-T cells differentiated into long-term memory effector cells, and seemed not to lose function even after repeated stimulation by HLA-G-expressing tumor cells. CONCLUSION We report for the first time that HLA-G, which is both a TSA and an ICP, constitutes a valid target for CAR-T cell therapy to specifically target and eliminate both tumor cells and HLA-G+ suppressive cells.
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MESH Headings
- Animals
- Antibodies, Monoclonal/genetics
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/metabolism
- Antigens, CD/metabolism
- Cell Differentiation
- Coculture Techniques
- Cytotoxicity, Immunologic
- HLA-G Antigens/immunology
- HLA-G Antigens/metabolism
- Humans
- Immunologic Memory
- Immunotherapy, Adoptive
- K562 Cells
- Leukemia, Erythroblastic, Acute/genetics
- Leukemia, Erythroblastic, Acute/immunology
- Leukemia, Erythroblastic, Acute/metabolism
- Leukemia, Erythroblastic, Acute/therapy
- Leukocyte Immunoglobulin-like Receptor B1/metabolism
- Memory T Cells/immunology
- Memory T Cells/metabolism
- Memory T Cells/transplantation
- Mice, Inbred NOD
- Mice, SCID
- Phenotype
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/metabolism
- Time Factors
- Tumor Microenvironment
- Xenograft Model Antitumor Assays
- Mice
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Affiliation(s)
- François Anna
- Preclinical Department, Invectys, Paris, France
- Molecular Virology and Vaccinology Unit, Virology Department, Pasteur Institute, Paris, Île-de-France, France
| | - Elodie Bole-Richard
- INSERM UMR1098 RIGHT Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besancon, Franche-Comté, France
- Université Bourgogne Franche-Comté, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, Besançon, France
| | - Joel LeMaoult
- Service de Recherche en Hémato-Immunologie (SRHI), CEA, Paris, France
- Université de Paris, Paris, Île-de-France, France
| | | | | | - Jean-Marie Certoux
- INSERM UMR1098 RIGHT Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besancon, Franche-Comté, France
- Université Bourgogne Franche-Comté, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, Besançon, France
| | - Philippe Souque
- Molecular Virology and Vaccinology Unit, Virology Department, Pasteur Institute, Paris, Île-de-France, France
| | - Francine Garnache
- INSERM UMR1098 RIGHT Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besancon, Franche-Comté, France
- Université Bourgogne Franche-Comté, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, Besançon, France
| | - Olivier Adotevi
- INSERM UMR1098 RIGHT Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besancon, Franche-Comté, France
- Université Bourgogne Franche-Comté, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, Besançon, France
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Trogocytosis between Non-Immune Cells for Cell Clearance, and among Immune-Related Cells for Modulating Immune Responses and Autoimmunity. Int J Mol Sci 2021; 22:ijms22052236. [PMID: 33668117 PMCID: PMC7956485 DOI: 10.3390/ijms22052236] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/21/2021] [Accepted: 02/21/2021] [Indexed: 12/21/2022] Open
Abstract
The term trogocytosis refers to a rapid bidirectional and active transfer of surface membrane fragment and associated proteins between cells. The trogocytosis requires cell-cell contact, and exhibits fast kinetics and the limited lifetime of the transferred molecules on the surface of the acceptor cells. The biological actions of trogocytosis include information exchange, cell clearance of unwanted tissues in embryonic development, immunoregulation, cancer surveillance/evasion, allogeneic cell survival and infectious pathogen killing or intercellular transmission. In the present review, we will extensively review all these aspects. In addition to its biological significance, aberrant trogocytosis in the immune system leading to autoimmunity and immune-mediated inflammatory diseases will also be discussed. Finally, the prospective investigations for further understanding the molecular basis of trogocytosis and its clinical applications will also be proposed.
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Kumano S, Okushi Y, Fujimoto K, Adachi H, Furuichi K, Yokoyama H. Role and expression of non-classical human leukocyte antigen-G in renal transplanted allografts. Clin Exp Nephrol 2021; 25:428-438. [PMID: 33398603 DOI: 10.1007/s10157-020-01999-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/19/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND The non-classical class I molecule human leukocyte antigen-G (HLA-G) has great potential to modulate the immune response. However, the mechanism underlying HLA-G induction remains unknown. Therefore, this study aimed to determine the factors that induce HLA-G expression on proximal tubular epithelial cells (pTECs) in renal transplanted allografts in vivo and in vitro. METHODS This study included 40 adult Japanese patients with renal allografts (35 and five patients with kidneys from living and deceased donors, respectively) who survived for at least 1 year. We evaluated HLA-G1/5 expression using an immunofluorescence method and investigated the induction of HLA-G expression in primary cultured human pTECs by cytokines and immunosuppressants. RESULTS The HLA-G expression was identified in the perinuclear region or on the basement membrane of pTECs of renal biopsy tissue in 12 (30%) of 40 patients at 2-4 weeks and at 1 year following transplantation. A reduction of 30% in the estimated glomerular filtration rate was lower in the HLA-G-positive group than that of the negative group (p = 0.016). Cox proportional hazard models also demonstrated that HLA-G1/5 expression on pTECs was an independent predictor of improved renal allograft function (hazard ratio, 0.189; 95% CI 0.041-0.850, p = 0.030). Interferon-beta was the most powerful inducer of HLA-G expression in vitro, whereas the immunosuppressants everolimus, tacrolimus, cyclosporin, and dexamethasone did not induce any expression. CONCLUSION Unlike immunosuppressants, acquired HLA-G expression might confer long-term renal preservation effects in renal transplanted allografts.
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Affiliation(s)
- Sho Kumano
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
| | - Yuki Okushi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Keiji Fujimoto
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Hiroki Adachi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Kengo Furuichi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Hitoshi Yokoyama
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
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Xu X, Zhou Y, Wei H. Roles of HLA-G in the Maternal-Fetal Immune Microenvironment. Front Immunol 2020; 11:592010. [PMID: 33193435 PMCID: PMC7642459 DOI: 10.3389/fimmu.2020.592010] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022] Open
Abstract
During pregnancy, the maternal uterus and fetus form a special microenvironment at the maternal-fetal interface to support fetal development. Extravillous trophoblasts (EVTs), differentiated from the fetus, invade into the decidua and interact with maternal cells. Human leukocyte antigen (HLA)-G is a non-classical MHC-I molecule that is expressed abundantly and specifically on EVTs in physiological conditions. Soluble HLA-G (sHLA-G) is also found in maternal blood, amniotic fluid, and cord blood. The abnormal expression and polymorphisms of HLA-G are related to adverse pregnancy outcomes such as preeclampsia (PE) and recurrent spontaneous abortion (RSA). Here we summarize current findings about three main roles of HLA-G during pregnancy, namely its promotion of spiral artery remodeling, immune tolerance, and fetal growth, all resulting from its interaction with immune cells. These findings are not only of great significance for the treatment of pregnancy-related diseases but also provide clues to tumor immunology research since HLA-G functions as a checkpoint in tumors.
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Affiliation(s)
- Xiuxiu Xu
- Hefei National Laboratory for Physical Sciences at Microscale, Division of Molecular Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Yonggang Zhou
- Hefei National Laboratory for Physical Sciences at Microscale, Division of Molecular Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China.,The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Hefei National Laboratory for Physical Sciences at Microscale, Division of Molecular Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
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Shi L, Li W, Liu Y, Chen Z, Hui Y, Hao P, Xu X, Zhang S, Feng H, Zhang B, Zhou S, Li N, Xiao L, Liu L, Ma L, Zhang X. Generation of hypoimmunogenic human pluripotent stem cells via expression of membrane-bound and secreted β2m-HLA-G fusion proteins. Stem Cells 2020; 38:1423-1437. [PMID: 32930470 DOI: 10.1002/stem.3269] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 07/24/2020] [Accepted: 08/11/2020] [Indexed: 01/16/2023]
Abstract
Allogeneic immune rejection is a major barrier for the application of human pluripotent stem cells (hPSCs) in regenerative medicine. A broad spectrum of immune cells, including T cells, natural killer (NK) cells, and antigen-presenting cells, which either cause direct cell killing or constitute an immunogenic environment, are involved in allograft immune rejection. A strategy to protect donor cells from cytotoxicity while decreasing the secretion of inflammatory cytokines of lymphocytes is still lacking. Here, we engineered hPSCs with no surface expression of classical human leukocyte antigen (HLA) class I proteins via beta-2 microglobulin (B2M) knockout or biallelic knockin of HLA-G1 within the frame of endogenous B2M loci. Elimination of the surface expression of HLA class I proteins protected the engineered hPSCs from cytotoxicity mediated by T cells. However, this lack of surface expression also resulted in missing-self response and NK cell activation, which were largely compromised by expression of β2m-HLA-G1 fusion proteins. We also proved that the engineered β2m-HLA-G5 fusion proteins were soluble, secretable, and capable of safeguarding low immunogenic environments by lowering inflammatory cytokines secretion in allografts. Our current study reveals a novel strategy that may offer unique advantages to construct hypoimmunogenic hPSCs via the expression of membrane-bound and secreted β2m-HLA-G fusion proteins. These engineered hPSCs are expected to serve as an unlimited cell source for generating universally compatible "off-the-shelf" cell grafts in the future.
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Affiliation(s)
- Lei Shi
- College of Animal Sciences, Zhejiang University, Hangzhou, People's Republic of China.,Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Wenjing Li
- College of Animal Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Yang Liu
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Zhenyu Chen
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Yi Hui
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Pengcheng Hao
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Xiangjie Xu
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Shuwei Zhang
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Hexi Feng
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Bowen Zhang
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Shanshan Zhou
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Nan Li
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Lei Xiao
- College of Animal Sciences, Zhejiang University, Hangzhou, People's Republic of China.,Shanghai SiDanSai Biotechnology Limited Company, Shanghai, People's Republic of China
| | - Ling Liu
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China.,Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, People's Republic of China
| | - Lin Ma
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China.,Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, People's Republic of China
| | - Xiaoqing Zhang
- Brain and Spinal Cord Clinical Research Center, Tongji University School of Medicine, Shanghai, People's Republic of China.,Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, Shanghai, People's Republic of China.,Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, People's Republic of China.,Key Laboratory of Reconstruction and Regeneration of Spine and Spinal Cord Injury, Ministry of Education, Shanghai, People's Republic of China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, People's Republic of China
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Contini P, Murdaca G, Puppo F, Negrini S. HLA-G Expressing Immune Cells in Immune Mediated Diseases. Front Immunol 2020; 11:1613. [PMID: 32983083 PMCID: PMC7484697 DOI: 10.3389/fimmu.2020.01613] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 06/17/2020] [Indexed: 12/12/2022] Open
Abstract
HLA-G is a HLA class Ib antigen that possesses immunomodulatory properties. HLA-G-expressing CD4+ and CD8+ T lymphocytes, NK cells, monocytes, and dendritic cells with immunoregulatory functions are present in small percentages of patients with physiologic conditions. Quantitative and qualitative derangements of HLA-G+ immune cells have been detected in several conditions in which the immune system plays an important role, such as infectious, neoplastic, and autoimmune diseases as well as in complications from transplants and pregnancy. These observations strongly support the hypothesis that HLA-G+ immune cells may be implicated in the complex mechanisms underlying the pathogenesis of these disorders.
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Affiliation(s)
| | | | - Francesco Puppo
- Department of Internal Medicine, University of Genoa, Genoa, Italy
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Loustau M, Anna F, Dréan R, Lecomte M, Langlade-Demoyen P, Caumartin J. HLA-G Neo-Expression on Tumors. Front Immunol 2020; 11:1685. [PMID: 32922387 PMCID: PMC7456902 DOI: 10.3389/fimmu.2020.01685] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/24/2020] [Indexed: 12/20/2022] Open
Abstract
HLA-G is known to modulate the immune system activity in tissues where physiological immune-tolerance is necessary (i.e., maternal-fetal interface, thymus, and cornea). However, the frequent neo-expression of HLA-G in many cancer types has been previously and extensively described and is correlated with a bad prognosis. Despite being an MHC class I molecule, HLA-G is highly present in tumor context and shows unique characteristics of tissue restriction of a Tumor Associated Antigen (TAA), and potent immunosuppressive activity of an Immune CheckPoint (ICP). Consequently, HLA-G appears to be an excellent molecular target for immunotherapy. Although the relevance of HLA-G in cancer incidence and development has been proven in numerous tumors, its neo-expression pattern is still difficult to determine. Indeed, the estimation of HLA-G's actual expression in tumor tissue is limited, particularly concerning the presence and percentage of the new non-canonical isoforms, for which detection antibodies are scarce or inexistent. Here, we summarize the current knowledge about HLA-G neo-expression and implication in various tumor types, pointing out the need for the development of new tools to analyze in-depth the HLA-G neo-expression patterns, opening the way for the generation of new monoclonal antibodies and cell-based immunotherapies.
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Affiliation(s)
| | - François Anna
- Invectys, Paris, France
- Molecular Virology and Vaccinology Unit, Virology Department, Institut Pasteur & CNRS URA 3015, Paris, France
| | - Raphaelle Dréan
- Invectys, Paris, France
- Molecular Retrovirology Unit, Institut Pasteur, CNRS, UMR 3569, Paris, France
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Merino AM, Kim H, Miller JS, Cichocki F. Unraveling exhaustion in adaptive and conventional NK cells. J Leukoc Biol 2020; 108:1361-1368. [PMID: 32726880 DOI: 10.1002/jlb.4mr0620-091r] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/08/2020] [Accepted: 06/16/2020] [Indexed: 12/16/2022] Open
Abstract
Immune exhaustion in T cells significantly impacts their ability to control malignancies and infections, and its discovery has led to revolutionary therapies for cancer in the form of checkpoint blockade. NK cells, like T cells, are lymphocytes that recognize virally infected and malignantly transformed cells. However, it remains unclear if NK cells are similarly susceptible to exhaustion. In this review, the aims are to summarize what is currently known and to identify key areas of variability that skew the scientific literature on NK cell exhaustion. A lack of consensus on the defining features of NK cell dysfunctional states such as senescence, suppression, and exhaustion has made a comparison between studies difficult. There are also significant differences in the biology of NK cell subsets with long-lived, adaptive NK cells sharing an epigenetic signature closer to memory CD8+ T cells than to conventional NK cells. Very different checkpoint receptor expression and effector functions have been shown in adaptive versus conventional NK cells chronically exposed to activating signals. Adaptive NK cells develop in individuals with cytomegalovirus (CMV) infection and well over half of the human population worldwide is CMV seropositive by adulthood. Despite this high prevalence, most studies do not account or control for this population. This may contribute to some of the variability reported in the literature on checkpoint receptor expression on NK cells. In this review, the protective role that exhaustion plays in T cells will also be discussed and the evidence for a similar phenomenon in NK cells will be examined.
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Affiliation(s)
- Aimee M Merino
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Hansol Kim
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jeffrey S Miller
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Frank Cichocki
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
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Krijgsman D, Roelands J, Hendrickx W, Bedognetti D, Kuppen PJK. HLA-G: A New Immune Checkpoint in Cancer? Int J Mol Sci 2020; 21:ijms21124528. [PMID: 32630545 PMCID: PMC7350262 DOI: 10.3390/ijms21124528] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/22/2020] [Accepted: 06/24/2020] [Indexed: 12/15/2022] Open
Abstract
Human leukocyte antigen G (HLA-G), known as a central protein in providing immune tolerance to the fetus in pregnant women, is also studied for a possible role in tumor development. Many studies have claimed HLA-G as a new immune checkpoint in cancer. Therefore, HLA-G and its receptors might be targets for immune checkpoint blockade in cancer immunotherapy. In order to substantiate that HLA-G is indeed an immune checkpoint in cancer, two important questions need to be answered: (1) To what extent is HLA-G expressed in the tumor by cancer cells? and (2) What is the function of HLA-G in cancer immune evasion? In this review, we discuss these questions. We agree that HLA-G is a potentially new immune checkpoint in cancer, but additional evidence is required to show the extent of intra-tumor and inter-tumor expression. These studies should focus on tumor expression patterns of the seven different HLA-G isoforms and of the receptors for HLA-G. Furthermore, specific roles for the different HLA-G isoforms should be established.
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Affiliation(s)
- Daniëlle Krijgsman
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (D.K.); (J.R.)
| | - Jessica Roelands
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (D.K.); (J.R.)
- Cancer Research Department, Research Branch, Sidra Medicine, Doha P.O. Box 26999, Qatar; (W.H.); (D.B.)
| | - Wouter Hendrickx
- Cancer Research Department, Research Branch, Sidra Medicine, Doha P.O. Box 26999, Qatar; (W.H.); (D.B.)
| | - Davide Bedognetti
- Cancer Research Department, Research Branch, Sidra Medicine, Doha P.O. Box 26999, Qatar; (W.H.); (D.B.)
| | - Peter J. K. Kuppen
- Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (D.K.); (J.R.)
- Correspondence: ; Tel.: +31-71-5264569
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