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1
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Guerra-Bauman F, Tseng JE, Latif A, Cohan C, Assalita J, Waheed A. "Pardon My Language": The Curious Case of a Bloody Sandwich and the John Cunningham Virus Reactivation in the Era of Immunomodulatory Drugs. Cureus 2024; 16:e72306. [PMID: 39583423 PMCID: PMC11585329 DOI: 10.7759/cureus.72306] [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] [Accepted: 10/24/2024] [Indexed: 11/26/2024] Open
Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare diagnosis associated with high mortality in different clinical settings. PML has been attributed to the reactivation of the John Cunningham (JC) virus (JCV). JCV typically affects patients with HIV/AIDS, solid organ and hematological malignancies, and those under treatment with immunomodulatory drugs (IMiDs) like pomalidomide. Currently, there are a limited number of reported cases of patients with multiple myeloma (MM) who developed PML reported in the literature, and one case report of a patient with MM diagnosed with PML in association with pomalidomide and daratumumab. Here, we describe a case of PML in a patient with MM status post autologous stem cell transplant (ASCT) on maintenance treatment with pomalidomide who presented with cognitive decline and aphasia. In an era of increased access to immunomodulatory therapies, physicians should be able to recognize this potential complication as discontinuation of the medication could be lifesaving.
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Affiliation(s)
| | - Jessica E Tseng
- Department of Family Medicine, Creighton University School of Medicine, Phoenix, USA
| | - Asfandyar Latif
- Department of Family Medicine, WellSpan Good Samaritan Hospital, Lebanon, USA
| | - Chloe Cohan
- Department of Family Medicine, Creighton University School of Medicine, Phoenix, USA
| | - Jason Assalita
- Department of Family Medicine, Family Medicine Residency Program, WellSpan Good Samaritan Hospital, Lebanon, USA
| | - Abdul Waheed
- Department of Family and Community Medicine, Creighton University School of Medicine, Phoenix, USA
- Department of Family Medicine, Dignity Health Medical Group, Gilbert, USA
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2
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Gao M, Liu X, Du M, Gu H, Xu H, Zhong X. Identification of immune cell infiltration and effective biomarkers of polycystic ovary syndrome by bioinformatics analysis. BMC Pregnancy Childbirth 2023; 23:377. [PMID: 37226082 DOI: 10.1186/s12884-023-05693-4] [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: 12/18/2022] [Accepted: 05/09/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Patients with polycystic ovary syndrome (PCOS) exhibit a chronic inflammatory state, which is often accompanied by immune, endocrine, and metabolic disorders. Clarification of the pathogenesis of PCOS and exploration of specific biomarkers from the perspective of immunology by evaluating the local infiltration of immune cells in the follicular microenvironment may provide critical insights into disease pathogenesis. METHODS In this study, we evaluated immune cell subsets and gene expression in patients with PCOS using data from the Gene Expression Omnibus database and single-sample gene set enrichment analysis. RESULTS In total, 325 differentially expressed genes were identified, among which TMEM54 and PLCG2 (area under the curve = 0.922) were identified as PCOS biomarkers. Immune cell infiltration analysis showed that central memory CD4+ T cells, central memory CD8+ T cells, effector memory CD4+ T cells, γδ T cells, and type 17 T helper cells may affect the occurrence of PCOS. In addition, PLCG2 was highly correlated with γδ T cells and central memory CD4+ T cells. CONCLUSIONS Overall, TMEM54 and PLCG2 were identified as potential PCOS biomarkers by bioinformatics analysis. These findings established a basis for further exploration of the immunological mechanisms of PCOS and the identification of therapeutic targets.
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Affiliation(s)
- Mengge Gao
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, 510600, China
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, Guangdong Province, China
- Department of Clinical Nutrition, Huadu District People's Hospital, Southern Medical University, 48 Xinhua Road, Huadu, Guangzhou, 510800, Guangdong, China
| | - Xiaohua Liu
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, 510600, China
| | - Mengxuan Du
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, 510600, China
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, Guangdong Province, China
| | - Heng Gu
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, 510600, China
| | - Hang Xu
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, 510600, China
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, Guangdong Province, China
| | - Xingming Zhong
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, 510600, China.
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, Guangdong Province, China.
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3
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Friedrich MJ, Neri P, Kehl N, Michel J, Steiger S, Kilian M, Leblay N, Maity R, Sankowski R, Lee H, Barakat E, Ahn S, Weinhold N, Rippe K, Bunse L, Platten M, Goldschmidt H, Müller-Tidow C, Raab MS, Bahlis NJ. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients. Cancer Cell 2023; 41:711-725.e6. [PMID: 36898378 DOI: 10.1016/j.ccell.2023.02.008] [Citation(s) in RCA: 119] [Impact Index Per Article: 59.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 11/02/2022] [Accepted: 02/08/2023] [Indexed: 03/11/2023]
Abstract
Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but the immunological mechanism and molecular determinants of primary and acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors of bone marrow-residing T cells in multiple myeloma patients undergoing BCMAxCD3 TCE therapy. We show that the immune repertoire reacts to TCE therapy with cell state-dependent clonal expansion and find evidence supporting the coupling of tumor recognition via major histocompatibility complex class I (MHC class I), exhaustion, and clinical response. We find the abundance of exhausted-like CD8+ T cell clones to be associated with clinical response failure, and we describe loss of target epitope and MHC class I as tumor-intrinsic adaptations to TCEs. These findings advance our understanding of the in vivo mechanism of TCE treatment in humans and provide the rationale for predictive immune-monitoring and conditioning of the immune repertoire to guide future immunotherapy in hematological malignancies.
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Affiliation(s)
- Mirco J Friedrich
- Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - Paola Neri
- Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, Canada; Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada
| | - Niklas Kehl
- Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Julius Michel
- Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Simon Steiger
- Division of Chromatin Networks, BioQuant Center & German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Michael Kilian
- Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Noémie Leblay
- Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada
| | - Ranjan Maity
- Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada
| | - Roman Sankowski
- Department of Neuropathology, Freiburg University Hospital, Freiburg, Germany
| | - Holly Lee
- Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, Canada; Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada
| | - Elie Barakat
- Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada
| | - Sungwoo Ahn
- Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada
| | - Niels Weinhold
- Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Karsten Rippe
- Division of Chromatin Networks, BioQuant Center & German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lukas Bunse
- Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Michael Platten
- Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Helmholtz Institute of Translational Oncology (HI-TRON), Mainz, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim Germany
| | - Hartmut Goldschmidt
- Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Carsten Müller-Tidow
- Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Marc-Steffen Raab
- Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Nizar J Bahlis
- Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, Canada; Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada.
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4
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Gonzalez-Montes Y, Rodriguez-Romanos R, Villavicencio A, Osca-Gelis G, González-Bártulos M, Llopis F, Clapes V, Oriol A, Sureda A, Escoda L, Sarrà J, Garzó A, Lloveras N, Díez I, Granada I, Gallardo D. Genetic variants of CTLA4 are associated with clinical outcome of patients with multiple myeloma. Front Immunol 2023; 14:1158105. [PMID: 37122695 PMCID: PMC10143497 DOI: 10.3389/fimmu.2023.1158105] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/29/2023] [Indexed: 05/02/2023] Open
Abstract
Immune dysfunction in patients with multiple myeloma (MM) affects both the innate and adaptive immune system. Molecules involved in the immune checkpoint pathways are essential to determine the ability of cancer cells to escape from the immune system surveillance. However, few data are available concerning the role of these molecules in predicting the kinetics of progression of MM. We retrospectively analysed polymorphisms of CTLA4 (rs231775 and rs733618), BTLA (rs9288953), CD28 (rs3116496), PD-1 (rs36084323 and rs11568821) and LAG-3 (rs870849) genes in 239 patients with newly diagnosed MM. Patients with a CTLA4 rs231775 AA/AG genotype showed a median progression-free survival (PFS) significantly lower than those with GG genotype (32.3 months versus 96.8 months respectively; p: 0.008). The 5-year PFS rate was 25% for patients with grouped AA and AG genotype vs 55.4% for patients with GG genotype. Multivariate analysis confirmed the CTLA4 rs231775 genotype as an independent risk factor for PFS (Hazard Ratio (HR): 2.05; 95% CI: 1.0-6.2; p: 0.047). Our results suggest that the CTLA4 genotype may identify patients with earlier progression of MM. This polymorphism could potentially be used as a prognostic biomarker.
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Affiliation(s)
- Yolanda Gonzalez-Montes
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
- *Correspondence: Yolanda Gonzalez-Montes,
| | - Rocío Rodriguez-Romanos
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
| | - Alicia Villavicencio
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
| | - Gemma Osca-Gelis
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
- Girona Cancer Registry, Oncology Coordination Plan, Catalan Institute of Oncology (RTH) ICO-ICS, Centre CIBER of Epidemiology and Public Health (CIBERESP), Girona, Spain
| | - Marta González-Bártulos
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
| | - Francesca Llopis
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
| | - Victòria Clapes
- Clinical Hematology Department, Institut Català d’Oncologia, L’Hospitalet, IDIBELL, Universitat de Barcelona, Hospitalet de LLobregat, Spain
| | - Albert Oriol
- Hematology Department, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Barcelona, Spain
| | - Anna Sureda
- Clinical Hematology Department, Institut Català d’Oncologia, L’Hospitalet, IDIBELL, Universitat de Barcelona, Hospitalet de LLobregat, Spain
| | - Lourdes Escoda
- Hematology Department, Institut Català d’Oncologia, Hospital Joan XXIII, Universitat Rovira i Virgili (URV), Tarragona, Spain
| | - Josep Sarrà
- Hematology Department, Institut Català d’Oncologia, Hospital Joan XXIII, Universitat Rovira i Virgili (URV), Tarragona, Spain
| | - Ana Garzó
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
| | - Natàlia Lloveras
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
| | - Isabel Díez
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
| | - Isabel Granada
- Hematology Department, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Barcelona, Spain
| | - David Gallardo
- Hematology Department, Institut Català d’Oncologia, Hospital Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona (IDIBGI), Josep Carreras Research Institute, Girona, Universitat de Girona, Girona, Spain
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5
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Yao L, Jayasinghe RG, Lee BH, Bhasin SS, Pilcher W, Doxie DB, Gonzalez-Kozlova E, Dasari S, Fiala MA, Pita-Juarez Y, Strausbauch M, Kelly G, Thomas BE, Kumar SK, Cho HJ, Anderson E, Wendl MC, Dawson T, D'souza D, Oh ST, Cheloni G, Li Y, DiPersio JF, Rahman AH, Dhodapkar KM, Kim-Schulze S, Vij R, Vlachos IS, Mehr S, Hamilton M, Auclair D, Kourelis T, Avigan D, Dhodapkar MV, Gnjatic S, Bhasin MK, Ding L. Comprehensive Characterization of the Multiple Myeloma Immune Microenvironment Using Integrated scRNA-seq, CyTOF, and CITE-seq Analysis. CANCER RESEARCH COMMUNICATIONS 2022; 2:1255-1265. [PMID: 36969740 PMCID: PMC10035369 DOI: 10.1158/2767-9764.crc-22-0022] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/09/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022]
Abstract
As part of the Multiple Myeloma Research Foundation (MMRF) immune atlas pilot project, we compared immune cells of multiple myeloma bone marrow samples from 18 patients assessed by single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to understand the concordance of measurements among single-cell techniques. Cell type abundances are relatively consistent across the three approaches, while variations are observed in T cells, macrophages, and monocytes. Concordance and correlation analysis of cell type marker gene expression across different modalities highlighted the importance of choosing cell type marker genes best suited to particular modalities. By integrating data from these three assays, we found International Staging System stage 3 patients exhibited decreased CD4+ T/CD8+ T cells ratio. Moreover, we observed upregulation of RAC2 and PSMB9, in natural killer cells of fast progressors compared with those of nonprogressors, as revealed by both scRNA-seq and CITE-seq RNA measurement. This detailed examination of the immune microenvironment in multiple myeloma using multiple single-cell technologies revealed markers associated with multiple myeloma rapid progression which will be further characterized by the full-scale immune atlas project. Significance scRNA-seq, CyTOF, and CITE-seq are increasingly used for evaluating cellular heterogeneity. Understanding their concordances is of great interest. To date, this study is the most comprehensive examination of the measurement of the immune microenvironment in multiple myeloma using the three techniques. Moreover, we identified markers predicted to be significantly associated with multiple myeloma rapid progression.
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Affiliation(s)
- Lijun Yao
- Washington University School of Medicine, Saint Louis, Missouri
| | | | - Brian H. Lee
- Icahn School of Medicine at Mt. Sinai, New York, New York
| | | | | | | | | | | | - Mark A. Fiala
- Washington University School of Medicine, Saint Louis, Missouri
| | - Yered Pita-Juarez
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | | | - Geoffrey Kelly
- Icahn School of Medicine at Mt. Sinai, New York, New York
| | | | | | - Hearn Jay Cho
- Icahn School of Medicine at Mt. Sinai, New York, New York
- Multiple Myeloma Research Foundation, Norwalk, Connecticut
| | | | | | - Travis Dawson
- Icahn School of Medicine at Mt. Sinai, New York, New York
| | - Darwin D'souza
- Icahn School of Medicine at Mt. Sinai, New York, New York
| | - Stephen T. Oh
- Washington University School of Medicine, Saint Louis, Missouri
| | - Giulia Cheloni
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Ying Li
- Mayo Clinic, Rochester, Minnesota
| | | | | | | | | | - Ravi Vij
- Washington University School of Medicine, Saint Louis, Missouri
| | - Ioannis S. Vlachos
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Shaadi Mehr
- Multiple Myeloma Research Foundation, Norwalk, Connecticut
| | - Mark Hamilton
- Multiple Myeloma Research Foundation, Norwalk, Connecticut
| | - Daniel Auclair
- Multiple Myeloma Research Foundation, Norwalk, Connecticut
| | | | - David Avigan
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | | | - Sacha Gnjatic
- Icahn School of Medicine at Mt. Sinai, New York, New York
| | | | - Li Ding
- Washington University School of Medicine, Saint Louis, Missouri
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6
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Ohmine K, Uchibori R. Novel immunotherapies in multiple myeloma. Int J Hematol 2022; 115:799-810. [PMID: 35583724 DOI: 10.1007/s12185-022-03365-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 11/24/2022]
Abstract
For a substantial period, options for the treatment of multiple myeloma (MM) were limited; however, the advent of novel therapies into clinical practice in the 1990s resulted in dramatic changes in the prognosis of the disease. Subsequently, new proteasome inhibitors and immunomodulators with innovations in efficacy and toxicity were introduced; yet there remains a spectrum of patients with poor outcomes with current treatment strategies. One of the causes of disease progression in MM is the loss of the ability of the dysfunctional immune environment to control virulent cell clones. In recent years, therapies to overcome the immunosuppressive tumor microenvironment and activate the host immune system have shown promise in MM, especially in relapsed and refractory disease. Clinical use of this approach has been approved for several immunotherapies, and a number of studies are currently underway in clinical trials. This review outlines three of the newest and most promising approaches being investigated to enhance the immune system against MM: (1) overcoming immunosuppression with checkpoint inhibitors, (2) boosting immunity against tumors with vaccines, and (3) enhancing immune effectors with adoptive cell therapy. Information on the latest clinical trials in each class will be provided, and further developments will be discussed.
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Affiliation(s)
- Ken Ohmine
- Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
- Division of Immuno-Gene and Cell Therapy (Takara Bio), Jichi Medical University, Shimotsuke, Tochigi, Japan.
| | - Ryosuke Uchibori
- Division of Immuno-Gene and Cell Therapy (Takara Bio), Jichi Medical University, Shimotsuke, Tochigi, Japan
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7
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Xu ZY, Yao XC, Shi XJ, Du XR. Significance of preoperative peripheral blood neutrophil-lymphocyte ratio in predicting postoperative survival in patients with multiple myeloma bone disease. World J Clin Cases 2022; 10:4380-4394. [PMID: 35663088 PMCID: PMC9125285 DOI: 10.12998/wjcc.v10.i14.4380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 12/30/2021] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The neutrophil-lymphocyte ratio (NLR) is often used to predict a poor prognosis in patients with tumors. This study investigated the preoperative peripheral blood NLR in predicting postoperative survival (POS) in patients with multiple myeloma bone disease (MMBD).
AIM To evaluate whether NLR can be used to predict the prognosis of MMBD patients after surgery.
METHODS The clinical data of 82 MMBD patients who underwent surgical treatments in Beijing Chao-yang Hospital were collected. The NLR was obtained from the absolute number of neutrophils and lymphocytes, calculated by the number of neutrophils and divided by the number of lymphocytes. The peripheral blood lymphocyte percentage was used as the major marker to analyze the change in characteristics of the immune statuses of multiple myeloma patients.
RESULTS The NLR cut-off values of NLR ≥ 3 patients and NLR ≥ 4 patients were significantly correlated with POS. The 3- and 5-year cumulative survival rates of the high NLR group (NLR ≥ 3 patients) were 19.1% and 0.0%, respectively, which were lower than those of the low NLR group (NLR < 3 patients) (67.2% and 48.3%) (P = 0.000). In the high NLR group, POS (14.86 ± 14.28) was significantly shorter than that in the low NLR group (32.68 ± 21.76). Univariate analysis showed that the lymphocyte percentage 1 wk after the operation (19.33 ± 9.08) was significantly lower than that before the operation (25.72 ± 11.02). Survival analysis showed that postoperative chemotherapy, preoperative performance status and preoperative peripheral blood NLR ≥ 3 were independent risk factors for POS.
CONCLUSION The preoperative peripheral blood NLR can predict POS in MMBD patients. MMBD patients with a high preoperative NLR (NLR ≥ 3) showed poor prognosis.
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Affiliation(s)
- Zi-Yu Xu
- Department of Orthopedics, Beijing Chao-Yang Hospital, Beijing 100020, China
| | - Xing-Chen Yao
- Department of Orthopedics, Beijing Chao-Yang Hospital, Beijing 100020, China
| | - Xiang-Jun Shi
- Department of Hematology, Beijing Chao-Yang Hospital, Beijing 100020, China
| | - Xin-Ru Du
- Department of Orthopedics, Beijing Chao-Yang Hospital, Beijing 100020, China
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8
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Chen Y, Cheng S, Dai J, Wang L, Xu Y, Peng X, Xie X, Peng C. Molecular mechanisms and applications of tea polyphenols: A narrative review. J Food Biochem 2021; 45:e13910. [PMID: 34426979 DOI: 10.1111/jfbc.13910] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/29/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022]
Abstract
Tea is a worldwide popular drink with high nutritional and medicinal values as it is rich in nutrients, such as polyphenols, amino acids, vitamins, glycosides, and so on. Among them, tea polyphenols (TPs) are the current research hotspot. TPs are known to have multiple biological activities such as anti-oxidation, anti-tumor, anti-inflammation, anti-bacteria, lowering lipid, and liver protection. By reviewing a large number of literatures, we explained the mechanism of TPs exerting biological activity and a wide range of applications. We also discussed the deficiencies and development potential of TPs, in order to provide theoretical reference and scientific basis for the subsequent development and utilization of TPs. PRACTICAL APPLICATIONS: We summarized the bioactivity mechanisms of TPs in anti-tumor, anti-oxidation, antibacterial, anti-inflammatory, lipid-lowering, and liver protection, focused on its application fields in food and medicine, and discussed the deficiency and development potential of current research on TPs, so as to provide a certain convenient way for scholars studying TPs. It is expected to contribute to the subsequent discovery of biological activity and the broadening of the field of TPs.
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Affiliation(s)
- Yan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Si Cheng
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiangang Dai
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liang Wang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yun Xu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyu Peng
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China.,College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Murdaca G, Allegra A, Paladin F, Calapai F, Musolino C, Gangemi S. Involvement of Alarmins in the Pathogenesis and Progression of Multiple Myeloma. Int J Mol Sci 2021; 22:9039. [PMID: 34445745 PMCID: PMC8396675 DOI: 10.3390/ijms22169039] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVE Multiple Myeloma (MM) is a haematological disease resulting from the neoplastic transformation of plasma cells. The uncontrolled growth of plasma cells in the bone marrow and the delivery of several cytokines causes bone erosion that often does not regress, even in the event of disease remission. MM is characterised by a multi-step evolutionary path, which starts with an early asymptomatic stage defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease. DATA SOURCES AND STUDY SELECTION We have selected scientific publications on the specific topics "alarmis, MGUS, and MM", drawing from PubMed. The keywords we used were alarmines, MGUS, MM, and immune system. RESULTS The analysis confirms the pivotal role of molecules such as high-mobility group box-1, heat shock proteins, and S100 proteins in the induction of neoangiogenesis, which represents a milestone in the negative evolution of MM as well as other haematological and non-haematological tumours. CONCLUSIONS Modulation of the host immune system and the inhibition of neoangiogenesis may represent the therapeutic target for the treatment of MM that is capable of promoting better survival and reducing the risk of RRMM.
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Affiliation(s)
- Giuseppe Murdaca
- Department of Internal Medicine, University of Genoa, Ospedale Policlinico San Martino IRCCS, 20132 Genoa, Italy;
| | - Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (A.A.); (C.M.)
| | - Francesca Paladin
- Department of Internal Medicine, University of Genoa, Ospedale Policlinico San Martino IRCCS, 20132 Genoa, Italy;
| | - Fabrizio Calapai
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy;
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (A.A.); (C.M.)
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy;
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10
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Zhaoyun L, Rong F. Predictive Role of Immune Profiling for Survival of Multiple Myeloma Patients. Front Immunol 2021; 12:663748. [PMID: 34290698 PMCID: PMC8287504 DOI: 10.3389/fimmu.2021.663748] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 06/23/2021] [Indexed: 01/10/2023] Open
Abstract
Despite new efficacy drugs and cell therapy have been used for multiple myeloma (MM) patients, some patients will relapse over time. We wonder the immune system play a vital role as well as MM cell during the development of disease. It is clear that the characteristic of myeloma cell is associated with the survival of MM patients. However, the link between the immune profiling and the prognosis of the disease is still not entirely clear. As more study focus on the role of immunity on multiple myeloma pathogenesis. There are plenty of study about the predictive role of immunity on the survival of multiple myeloma patients. Up to mow, the majority reviews published have focused on the immunotherapy and immune pathogenesis. It is indispensable to overlook the predictive role of immunity on multiple myeloma patients. Here, we give a review of vital previous works and recent progress related to the predictive role of immune profiling on multiple myeloma, such as absolute lymphocyte count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocytes and cytokines.
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Affiliation(s)
- Liu Zhaoyun
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Fu Rong
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
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11
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Shih LC, Chang WS, Lee HT, Wang YC, Wang ZH, Chao CY, Yu CC, Lin HY, Shen TC, Kuo CC, Tsai CW, Bau DAT. Interaction of Interleukin-16 Genotypes With Betel Quid Chewing Behavior on Oral Cancer in Taiwan. In Vivo 2021; 34:1759-1764. [PMID: 32606144 DOI: 10.21873/invivo.11969] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIM Interleukin-16 (IL-16) is reported to play an important role in inflammation, carcinogenesis and tumoricidal processes, however, the contribution of IL-16 genotype to oral carcinogenesis is still largely unrevealed. Thus, the study aimed to investigate the contribution of IL-16 genotypes to Taiwan oral cancer risk. MATERIALS AND METHODS The genotypes of IL-16 rs4778889, rs11556218, and rs4072111 were revealed among 958 oral cancer cases and 958 control subjects by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). RESULTS First, the distributions of genotypic (p=0.0004) and allelic (p=0.0001) frequencies of IL-16 rs11556218 were significantly different between the case and control groups. In detail, the frequencies of IL-16 rs11556218 TG and GG were 28.1 and 5.8%, respectively, among oral cancer patients, significantly higher compared to those among controls (25.0% and 2.7%, respectively). Second, no difference was observed regarding IL-16 rs4778889 or IL-16 rs4072111. Last, there was a synergistic effect of betel quid chewing behavior and risky IL-16 rs11556218 genotype on oral cancer risk. CONCLUSION The study indicates that the IL-16 rs11556218 G allele synergistically interacts with betel quid chewing behavior, contributing to increased risk of oral cancer in Taiwanese.
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Affiliation(s)
- Liang-Chun Shih
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.,Department of Otolaryngology, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Wen-Shin Chang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Hsu-Tung Lee
- Cancer Prevention Center, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.,Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C
| | - Yun-Chi Wang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Zhi-Hong Wang
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan, R.O.C
| | - Che-Yi Chao
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan, R.O.C
| | - Chien-Chih Yu
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.,School of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C
| | - Hui-Yi Lin
- School of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C
| | - Te-Chun Shen
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Chien-Chung Kuo
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.
| | - Chia-Wen Tsai
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C. .,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - DA-Tian Bau
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C. .,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.,Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, R.O.C
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12
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Wu MF, Wang YC, Shen TC, Chang WS, Li HT, Liao CH, Gong CL, Wang ZH, Tsai CW, Hsia TC, Bau DAT. Significant Association of Interleukin-16 Genetic Variations to Taiwanese Lung Cancer. In Vivo 2021; 34:1117-1123. [PMID: 32354900 DOI: 10.21873/invivo.11883] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/02/2020] [Accepted: 03/06/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIM Interleukin-16 has been reported to exhibit tumoricidal effects, however, the contribution of IL-16 genotypes to lung cancer is still largely unrevealed. This study aimed at investigating whether IL-16 genotypes contribute to lung cancer susceptibility. MATERIALS AND METHODS IL-16 rs4778889, rs11556218, and rs4072111 genotypic characteristics were determined among 358 lung cancer patients and 716 controls via the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS The highlight finding is that the distributions of genotypic (p=8.6E-10) and allelic (p=0.0001) frequencies of IL-16 rs11556218 was significantly different between cases and controls. In detail, the frequencies of IL-16 rs11556218 heterozygous variant TG and homozygous variant GG were 36.6 and 7.3% among the lung cancer patients, significantly higher than those among the controls (22.5% and 2.6%). On the other way, no difference was observed regarding IL-16 rs4778889 or IL-16 rs4072111. CONCLUSION The present study indicates IL-16 rs11556218 G allele is significantly associated with increased Taiwan lung cancer risk.
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Affiliation(s)
- Meng-Feng Wu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.,Division of Chest Surgery, Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, R.O.C
| | - Yun-Chi Wang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Te-Chun Shen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Wen-Shin Chang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Hsin-Ting Li
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Cheng-Hsi Liao
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Chi-Li Gong
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Zhi-Hong Wang
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan, R.O.C
| | - Chia-Wen Tsai
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C. .,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Te-Chun Hsia
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C. .,Department of Respiratory Therapy, China Medical University, Taichung, Taiwan, R.O.C.,Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - DA-Tian Bau
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C. .,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.,Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, R.O.C
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13
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Kaur K, Ko MW, Ohanian N, Cook J, Jewett A. Osteoclast-expanded super-charged NK-cells preferentially select and expand CD8+ T cells. Sci Rep 2020; 10:20363. [PMID: 33230147 PMCID: PMC7683603 DOI: 10.1038/s41598-020-76702-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023] Open
Abstract
Osteoclasts (OCs) and much less dendritic cells (DCs) induce significant expansion and functional activation of NK cells, and furthermore, the OC-expanded NK cells preferentially increase the expansion and activation of CD8+ T cells by targeting CD4+ T cells. When autologous OCs were used to expand patient NK cells much lower percentages of expanded CD8+ T cells, decreased numbers of expanded NK cells and decreased functions of NK cells could be observed, and the addition of allogeneic healthy OCs increased the patients' NK function. Mechanistically, OC-expanded NK cells were found to lyse CD4+ T cells but not CD8+ T cells suggesting potential selection of CD8+ T cells before their expansion by OC activated NK cells. In agreement, Increased IFN-γ secretion, and NK cell-mediated cytotoxicity and higher percentages of CD8+ T cells, in various tissue compartments of oral tumor-bearing hu-BLT mice in response to immunotherapy by OC-expanded NK cells were observed. Thus, our results indicate an important relationship between NK and CD8+ T cells.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA
| | - Nick Ohanian
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA
| | - Jessica Cook
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA.
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA.
- The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
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14
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Papadimitriou K, Tsakirakis N, Malandrakis P, Vitsos P, Metousis A, Orologas-Stavrou N, Ntanasis-Stathopoulos I, Kanellias N, Eleutherakis-Papaiakovou E, Pothos P, Fotiou D, Gavriatopoulou M, Kastritis E, Dimopoulos MA, Terpos E, Tsitsilonis OE, Kostopoulos IV. Deep Phenotyping Reveals Distinct Immune Signatures Correlating with Prognostication, Treatment Responses, and MRD Status in Multiple Myeloma. Cancers (Basel) 2020; 12:E3245. [PMID: 33158030 PMCID: PMC7692501 DOI: 10.3390/cancers12113245] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/16/2020] [Accepted: 10/29/2020] [Indexed: 12/16/2022] Open
Abstract
Despite recent advances, Multiple Myeloma (MM) remains an incurable disease with apparent heterogeneity that may explain patients' variable clinical outcomes. While the phenotypic, (epi)genetic, and molecular characteristics of myeloma cells have been thoroughly examined, there is limited information regarding the role of the bone marrow (BM) microenvironment in the natural history of the disease. In the present study, we performed deep phenotyping of 32 distinct immune cell subsets in a cohort of 94 MM patients to reveal unique immune profiles in both BM and peripheral blood (PB) that characterize distinct prognostic groups, responses to induction treatment, and minimal residual disease (MRD) status. Our data show that PB cells do not reflect the BM microenvironment and that the two sites should be studied independently. Adverse ISS stage and high-risk cytogenetics were correlated with distinct immune profiles; most importantly, BM signatures comprised decreased tumor-associated macrophages (TAMs) and erythroblasts, whereas the unique Treg signatures in PB could discriminate those patients achieving complete remission after VRd induction therapy. Moreover, MRD negative status was correlated with a more experienced CD4- and CD8-mediated immunity phenotype in both BM and PB, thus highlighting a critical role of by-stander cells linked to MRD biology.
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Affiliation(s)
- Konstantinos Papadimitriou
- Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece; (K.P.); (N.T.); (P.V.); (A.M.); (N.O.-S.); (P.P.)
| | - Nikolaos Tsakirakis
- Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece; (K.P.); (N.T.); (P.V.); (A.M.); (N.O.-S.); (P.P.)
| | - Panagiotis Malandrakis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Panagiotis Vitsos
- Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece; (K.P.); (N.T.); (P.V.); (A.M.); (N.O.-S.); (P.P.)
| | - Andreas Metousis
- Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece; (K.P.); (N.T.); (P.V.); (A.M.); (N.O.-S.); (P.P.)
| | - Nikolaos Orologas-Stavrou
- Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece; (K.P.); (N.T.); (P.V.); (A.M.); (N.O.-S.); (P.P.)
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Nikolaos Kanellias
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Evangelos Eleutherakis-Papaiakovou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Panagiotis Pothos
- Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece; (K.P.); (N.T.); (P.V.); (A.M.); (N.O.-S.); (P.P.)
| | - Despina Fotiou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Meletios-Athanasios Dimopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Evangelos Terpos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (P.M.); (I.N.-S.); (N.K.); (E.E.-P.); (D.F.); (M.G.); (E.K.); (M.-A.D.); (E.T.)
| | - Ourania E. Tsitsilonis
- Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece; (K.P.); (N.T.); (P.V.); (A.M.); (N.O.-S.); (P.P.)
| | - Ioannis V. Kostopoulos
- Department of Biology, School of Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece; (K.P.); (N.T.); (P.V.); (A.M.); (N.O.-S.); (P.P.)
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15
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Shi Q, Wu C, Han W, Zhao S, Wu Y, Jin Y, Qu X, Li J, Zhang R, Chen L. Clinical significance of CD200 expression in newly diagnosed multiple myeloma patients and dynamic changing during treatment. Leuk Lymphoma 2020; 62:709-715. [PMID: 33108911 DOI: 10.1080/10428194.2020.1839653] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The aim of our study was to determine the impact of CD200 expression in newly diagnosed myltiple myeloma (MM) patients. CD200+ patients had significantly shorter median overall survival time (OS) than CD200- patients (41.0 months vs. not reached, p = .009). The ratio of CD4+ to CD8+ T cells was lower in CD200+ patients and this reduction was significantly related to the increase of CD8+ T cells (p = .021). Moreover, we analyzed dynamic changes of CD200 expression in 47 CD200+ patients during treatment. Thirty-eight (80.9%) patients switched to CD200- during treatment. Those patients had a favorable survival compared with the others (median OS, 65.0 vs. 32.0 months, p < .001; median PFS, 29.0 vs. 11.5 months, p = .027). We concluded that CD200 expression is an independent marker for MM prognostic estimation during treatment.
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Affiliation(s)
- Qinglin Shi
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Chao Wu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Wenmin Han
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Sishu Zhao
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yujie Wu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yuanyuan Jin
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Xiaoyan Qu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jianyong Li
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Run Zhang
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Lijuan Chen
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
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16
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Miao L, Wei XL, Zhao Q, Qi J, Ren C, Wu QN, Wei DL, Liu J, Wang FH, Xu RH. p.P476S mutation of RBPJL inhibits the efficacy of anti-PD-1 therapy in oesophageal squamous cell carcinoma by blunting T-cell responses. Clin Transl Immunology 2020; 9:e1172. [PMID: 32994998 PMCID: PMC7507108 DOI: 10.1002/cti2.1172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022] Open
Abstract
Objectives Anti-PD-1 immune checkpoint blockade represents the onset of a new era in cancer immunotherapy. However, robust predictors are necessary for screening patients with immune checkpoint-responsive oesophageal squamous cell carcinoma (ESCC). Methods We obtained biopsy samples from an ESCC patient with mixed responses. The expression of CD4, CD8, CD68, PD-L1, RBPJL and IL-16 was analysed by immunohistochemistry, and the correlation with prognostic value was obtained from the GEPIA portal. T-cell functions were examined by flow cytometry, MTS and transwell assays. The secreted cytokines were identified using an Inflammation Array Kit. The concentration of soluble IFN-γ was measured by enzyme-linked immunosorbent assay. The clinical benefit of RBPJL was examined in a PBMC xenograft mouse model. Results The patient had an exceptional clinical response with shrinkage of the primary oesophageal and lung metastatic lesions as well as enlargement of liver metastatic lesions after toripalimab monotherapy. Four liver-specific gene mutations were identified. RBPJL showed better response to toripalimab in the PBMC cell-derived xenograft (CDX) ESCC model. Conditional medium from RBPJL overexpression induced chemotaxis and proliferation of T lymphocytes, as well as Th2/Th1 differentiation through the RBPJL-NF-κB-IL-16 axis in vitro. These functions were all inhibited by the p.P476S mutation of RBPJL (RBPJL (p.P476S)). Conclusions We report for the first time that RBPJL (p.P476S) promotes tumor growth in ESCC and inhibits the efficacy of anti-PD-1 therapy through blunting T-cell responses. Our findings provide a potential new predictor for evaluating the efficacy of anti-PD-1 therapy in ESCC patients.
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Affiliation(s)
- Lei Miao
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China.,Department of Pediatric Surgery Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou China
| | - Xiao-Li Wei
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China.,Department of Medical Oncology Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China
| | - Qi Zhao
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China
| | - JingJing Qi
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China
| | - Chao Ren
- Department of Medical Oncology Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China
| | - Qi-Nian Wu
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China.,Department of Pathology Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China
| | - Da-Liang Wei
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China
| | - Jia Liu
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China
| | - Feng-Hua Wang
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Collaborative Innovation Center for Cancer Medicine Guangzhou China.,Precision Diagnosis and Treatment for Gastrointestinal Cancer Chinese Academy of Medical Sciences Guangzhou China
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17
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de Souza VH, de Alencar JB, Tiyo BT, Alves HV, Vendramini ECL, Sell AM, Visentainer JEL. Association of functional IL16 polymorphisms with cancer and cardiovascular disease: a meta-analysis. Oncotarget 2020; 11:3405-3417. [PMID: 32934782 PMCID: PMC7486693 DOI: 10.18632/oncotarget.27715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 08/05/2020] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Interleukin-16 (IL-16) is a chemotactic cytokine that is found to increase in Cancer and cardiovascular diseases (CVD). Single nucleotide polymorphisms (SNPs) in IL16 were associated with diseases. Thus, we conducted a systematic review and meta-analysis to evaluate possible associations between IL16 rs4778889, rs11556218, rs4072111, and rs1131445 SNPs and the risk for cancer or CVD. MATERIALS AND METHODS This study was performed according to the PRISMA statement. Medline, Web of Science, and Scopus databases were systematically reviewed, and a meta-analysis was conducted. RESULTS The analysis comprised 6386 individuals with cancer and 2415 with CVD. The SNP rs11556218 was significantly associated with an increased risk for cancer in Chinese in different genetic inheritance models. Also, to the best of our knowledge, this is the first meta-analysis to show an association of rs4778889 with an increased risk of gastric cancer and rs11556218 with an increased risk of CVD in Chinese. CONCLUSIONS Our meta-analysis suggested that the SNPs rs11556218 and rs4778889 of IL16 were associated with an increased risk for cancer in Chinese and rs11556218 with increased risk for CVD in Chinese, highlighting the need for further studies on the impact of these polymorphisms on cancer treatment and surveillance.
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Affiliation(s)
- Victor Hugo de Souza
- Post Graduation Program in Biosciences and Physiopathology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil
| | - Josiane Bazzo de Alencar
- Post Graduation Program in Biosciences and Physiopathology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil
| | - Bruna Tiaki Tiyo
- Post Graduation Program in Biosciences and Physiopathology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil
| | - Hugo Vicentin Alves
- Post Graduation Program in Biosciences and Physiopathology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil
| | - Evelyn Castillo Lima Vendramini
- Post Graduation Program in Biosciences and Physiopathology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil
| | - Ana Maria Sell
- Post Graduation Program in Biosciences and Physiopathology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil.,Laboratory of Immunogenetics, Basic Health Sciences Department, State University of Maringá, Paraná, Brazil
| | - Jeane Eliete Laguila Visentainer
- Post Graduation Program in Biosciences and Physiopathology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil.,Laboratory of Immunogenetics, Basic Health Sciences Department, State University of Maringá, Paraná, Brazil
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18
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Gu Y, Jin Y, Ding J, Yujie W, Shi Q, Qu X, Zhao S, Li J, Lijuan C. Low absolute CD4 + T cell counts in peripheral blood predict poor prognosis in patients with newly diagnosed multiple myeloma. Leuk Lymphoma 2020; 61:1869-1876. [PMID: 32324088 DOI: 10.1080/10428194.2020.1751840] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The T lymphocyte system plays an active role in tumor immunosurveillance in multiple myeloma (MM), and abnormal T lymphocyte populations are often observed in patients with MM. In the current study, we evaluated the prognostic impact of abnormal T lymphocyte subset distributions in patients with newly diagnosed MM (NDMM). Between December 2012 to October 2016, 110 NDMM patients were included in this study. Multiparameter flow cytometry was applied to quantitatively analysis the peripheral blood T lymphocyte subsets, including CD4+ T cell, CD8+ T cell, and CD4/CD8 ratio. Survival analyses were performed based on the patients' clinical data and the quantity of T lymphocyte subsets. The median follow-up time was 27.0 months (range, 2.5-66). Baseline percentages and absolute CD4+ T cell counts and the CD4/CD8 ratio were positively correlated with both overall survival (OS) and progression-free survival (PFS) according to Kaplan-Meier curves (p < .05). In the multivariate COX analysis, lower CD4+ T cell count was an independent unfavorable factor in predicting both OS (p = .016) and PFS (p = .010). Furthermore, lower CD4/CD8 ratio was an independent adverse prognostic factor for shorter PFS (p = .017). These results suggested that T lymphocyte subsets were crucial indicators in correlation with MM patients' prognosis. Low CD4+ T cell counts and CD4/CD8 ratio were independent unfavorable prognostic predictors for patients with MM at diagnosis.
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Affiliation(s)
- Yan Gu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yuanyuan Jin
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jie Ding
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Wu Yujie
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Qinglin Shi
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Xiaoyan Qu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Sishu Zhao
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jianyong Li
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Chen Lijuan
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Key Laboratory of Hematology, Collaborative Innovation Center for Cancer Personalized Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
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19
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Tamura H, Ishibashi M, Sunakawa-Kii M, Inokuchi K. PD-L1-PD-1 Pathway in the Pathophysiology of Multiple Myeloma. Cancers (Basel) 2020; 12:E924. [PMID: 32290052 PMCID: PMC7226506 DOI: 10.3390/cancers12040924] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 04/03/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
PD-L1 expressed on tumor cells contributes to disease progression with evasion from tumor immunity. Plasma cells from multiple myeloma (MM) patients expressed higher levels of PD-L1 compared with healthy volunteers and monoclonal gammopathy of undetermined significance (MGUS) patients, and its expression is significantly upregulated in relapsed/refractory patients. Furthermore, high PD-L1 expression is induced by the myeloma microenvironment and PD-L1+ patients with MGUS and asymptomatic MM tend to show disease progression. PD-L1 expression on myeloma cells was associated with more proliferative potential and resistance to antimyeloma agents because of activation of the Akt pathway through PD-1-bound PD-L1 in MM cells. Those data suggest that PD-L1 plays a crucial role in the disease progression of MM.
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Affiliation(s)
- Hideto Tamura
- Division of Diabetes, Endocrinology and Hematology, Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Saitama 343-8555, Japan
- Department of Hematology, Nippon Medical School, Tokyo 113-8603, Japan; (M.S.-K.); (K.I.)
| | - Mariko Ishibashi
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8603, Japan;
| | - Mika Sunakawa-Kii
- Department of Hematology, Nippon Medical School, Tokyo 113-8603, Japan; (M.S.-K.); (K.I.)
| | - Koiti Inokuchi
- Department of Hematology, Nippon Medical School, Tokyo 113-8603, Japan; (M.S.-K.); (K.I.)
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20
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Association of the IL16 Asn1147Lys polymorphism with intravenous immunoglobulin resistance in Kawasaki disease. J Hum Genet 2020; 65:421-426. [PMID: 31965063 DOI: 10.1038/s10038-020-0721-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 12/27/2019] [Accepted: 01/05/2020] [Indexed: 01/21/2023]
Abstract
Kawasaki disease (KD) is an acute, self-limited vasculitis, mainly affecting children younger than 5 years old, with accompanying fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) is the standard treatment for KD; however, ~15% of patients are resistant to IVIG treatment. To identify protein coding genetic variants influencing IVIG resistance, we re-analyzed our previous genome-wide association study (GWAS) data from 296 patients with KD, including 101 IVIG non-responders and 195 IVIG responders. Five nonsynonymous SNPs (nsSNPs) in five immune-related genes, including a previously reported SAMD9L nsSNP (rs10488532; p.Val266Ile), were associated with IVIG non-response (odds ratio [OR] = 1.89-3.46, P = 0.0109-0.0035). In a replication study of the four newly-identified nsSNPs, only one in the interleukin 16 (IL16) gene (rs11556218, p.Asn1147Lys) showed a trend of association with IVIG non-response (OR = 1.54, P = 0.0078). The same IL16 nsSNP was more significantly associated with IVIG non-response in combined analysis of all data (OR = 1.64, P = 1.25 × 10-4). Furthermore, risk allele combination of the IL16 CT and SAMD9L TT nsSNP genotypes exhibited a very strong effect size (OR = 9.19, P = 3.63 × 10-4). These results implicate IL16 as involved in the mechanism of IVIG resistance in KD.
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21
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Abstract
Multiple myeloma (MM) is a B-cell malignancy characterized by the abnormal proliferation of clonal plasma cells in the bone marrow leading to end-organ manifestations. Despite the advancement in the therapy and care of patients with MM, relapse and resistance to standard therapy remain significant. The development of immunotherapy as a treatment modality for many types of cancers has led investigators to explore its use in MM in order to elicit myeloma-targeted immune responses, especially given that immune dysregulation is an underlying feature in the pathogenesis and progression of MM. In this concise review, we discuss the different advances in the immune-based therapy of MM, from immunomodulation, vaccines, to monoclonal antibodies, checkpoint inhibitors, adoptive T-cell therapies, and future promising therapies under investigation.
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22
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Yan H, Zheng G, Qu J, Liu Y, Huang X, Zhang E, Cai Z. Identification of key candidate genes and pathways in multiple myeloma by integrated bioinformatics analysis. J Cell Physiol 2019; 234:23785-23797. [PMID: 31215027 PMCID: PMC6771956 DOI: 10.1002/jcp.28947] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 12/16/2022]
Abstract
Multiple myeloma (MM) is a common hematologic malignancy for which the underlying molecular mechanisms remain largely unclear. This study aimed to elucidate key candidate genes and pathways in MM by integrated bioinformatics analysis. Expression profiles GSE6477 and GSE47552 were obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) with p < .05 and [logFC] > 1 were identified. Functional enrichment, protein–protein interaction network construction and survival analyses were then performed. First, 51 upregulated and 78 downregulated DEGs shared between the two GSE datasets were identified. Second, functional enrichment analysis showed that these DEGs are mainly involved in the B cell receptor signaling pathway, hematopoietic cell lineage, and NF‐kappa B pathway. Moreover, interrelation analysis of immune system processes showed enrichment of the downregulated DEGs mainly in B cell differentiation, positive regulation of monocyte chemotaxis and positive regulation of T cell proliferation. Finally, the correlation between DEG expression and survival in MM was evaluated using the PrognoScan database. In conclusion, we identified key candidate genes that affect the outcomes of patients with MM, and these genes might serve as potential therapeutic targets.
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Affiliation(s)
- Haimeng Yan
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Gaofeng Zheng
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianwei Qu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yang Liu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xi Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Enfan Zhang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China
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23
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Li L, Wang L. Multiple Myeloma: What Do We Do About Immunodeficiency? J Cancer 2019; 10:1675-1684. [PMID: 31205523 PMCID: PMC6548011 DOI: 10.7150/jca.29993] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/30/2019] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma (MM) is an incurable hematological malignancy. Immunodeficiency results in the incapability of immunity to eradicate both tumor cells and pathogens. Immunotherapies along with antibiotics and other anti-infectious agents are applied as substitutes for immunity in MM. Immunotherapies including monoclonal antibodies, immune checkpoints inhibitors, affinity- enhanced T cells, chimeric antigen receptor T cells and dendritic cell vaccines are revolutionizing MM treatment. By suppressing the pro-inflammatory milieu and pathogens, prophylactic and therapeutic antibiotics represent anti-tumor and anti-infection properties. It is expected that deeper understanding of infection, immunity and tumor physio-pathologies in MM will accelerate the optimization of combined therapies, thus improving prognosis in MM.
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Affiliation(s)
- Linrong Li
- Second Clinical Medical College, Southern Medical University, Guangzhou, China
| | - Liang Wang
- Department of Hematology, ZhuJiang Hospital of Southern Medical University, Guangzhou, China
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24
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Deng X, Fu Y, Luo S, Luo X, Wang Q, Hu M, Ma F, Ma CW, Zhou L. Polysaccharide from Radix Codonopsis has beneficial effects on the maintenance of T-cell balance in mice. Biomed Pharmacother 2019; 112:108682. [PMID: 30797152 DOI: 10.1016/j.biopha.2019.108682] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 02/09/2019] [Accepted: 02/10/2019] [Indexed: 01/06/2023] Open
Abstract
Immunity due to immune balance contributes to disease prevention and treatment. Radix Codonopsis polysaccharide (RCP) is isolated from the root of the Chinese herb Codonopsis pilosula. Previous studies have indicated that RCP has immunomodulatory activities; however, the effects of RCP on immunity, especially immune balance, are still largely unknown. In the present study, we investigated the effects of RCP on T-cell balance in mice. The mice were pretreated intragastrically with or without RCP for 15 days and injected with hydrocortisone on days 10-15 to disturb the immune system. The spleen and thymus were weighed and used to calculate immune organ indexes. The percentages of CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells, regulatory T cells (Tregs) and Th17 cells in peripheral blood were assayed by flow cytometry. Pro-inflammatory and anti-inflammatory cytokines, TNF-α, IL-1β and IL-10, in serum were determined by enzyme-linked immunosorbent assay (ELISA) kits. The results showed that RCP pretreatment could maintain the homeostasis of CD8+ T cells, Tregs, Th17 cells, TNF-α, IL-1β and IL-10 in hydrocortisone-treated mice. Furthermore, RCP pretreatment maintained the immune balance of CD4+/CD8+ T cells, Th1/Th2 cells, Tregs/Th17 cells, IL-10/TNF-α and IL-10/IL-1β. Taken together, RCP pretreatment had beneficial effects on the maintenance of T-cell balance against hydrocortisone disturbance in mice and potential to be developed into novel functional food.
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Affiliation(s)
- Xiangliang Deng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510663, China; School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yajun Fu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Shuang Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Xia Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Qing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Minghua Hu
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510663, China
| | - Fangli Ma
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510663, China
| | - Chung Wah Ma
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510663, China.
| | - Lian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
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25
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Immunotherapeutic Approaches for Multiple Myeloma: Where Are We Now? Curr Hematol Malig Rep 2019; 14:1-10. [PMID: 30666505 DOI: 10.1007/s11899-019-0492-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
PURPOSE OF REVIEW The treatment landscape for multiple myeloma has evolved rapidly with the availability of multiple new drugs; however, although patient survival has improved, the disease remains incurable. Multiple myeloma is characterized by the unregulated growth of malignant plasma cells accompanied by immune dysfunction as well as disrupted immune surveillance mechanisms. Here, we analyze clinical modalities, with a focus on monoclonal antibodies and adoptive cellular therapy that enhance patients' immune systems and overcome these defects. RECENT FINDINGS Early clinical trials with PD-1 inhibitors were promising, but randomized phase III trials with immunomodulatory drugs showed increased toxicities. Monoclonal antibodies targeting surface antigens led to substantial clinical efficiency in relapsed myeloma. Chimeric antigen receptor (CAR) T cell therapy for multiple myeloma represents a significant advance, as exciting and dramatic responses in early clinical trials have been seen. Immunotherapeutic approaches are promising and can augment or replace the current standard of care, with the potential to offer extended survival for myeloma patients.
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26
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Oscillating expression of interleukin-16 in multiple myeloma is associated with proliferation, clonogenic growth, and PI3K/NFKB/MAPK activation. Oncotarget 2018; 8:49253-49263. [PMID: 28512269 PMCID: PMC5564765 DOI: 10.18632/oncotarget.17534] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 03/14/2017] [Indexed: 12/27/2022] Open
Abstract
Multiple myeloma (MM) is an incurable hematologic malignancy emerging from a plasma cell clone located in the bone marrow and is characterized by a high rate of fatal relapses after initially effective treatment. We have previously identified Interleukin-16 (IL-16) as an important factor promoting the proliferation of MM cells. We demonstrate here an upregulated, periodic expression, and secretion of IL-16 by MM cells leading to high extracellular IL-16 levels. The level of IL-16 released from a given MM cell line correlated with its proliferative activity. Establishing an inducible knockdown system and performing gene expression arrays we observed an association between IL-16 expression and activation of PI3, NFκB and MAP kinase pathways and, specifically, genes involved in tumor cell proliferation. Functional assays showed that IL-16 knockdown reduced the proliferative activity with a significant delay in cell cycle progression to G2 phase of conventional MM cells and completely suppressed the growth of clonogenic MM cells, which are suspected to be responsible for the high relapse rates in MM. Overall, our results demonstrate that tumor-regenerating MM cells may be particularly susceptible to IL-16 neutralization, suggesting an important role of anti-IL-16 therapies in the treatment of MM, particularly in combination with existing strategies targeting the bulk of myeloma cells.
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27
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Fostier K, Caers J, Meuleman N, Broos K, Corthals J, Thielemans K, Schots R, De Keersmaecker B. Impact of lenalidomide maintenance on the immune environment of multiple myeloma patients with low tumor burden after autologous stem cell transplantation. Oncotarget 2018; 9:20476-20489. [PMID: 29755666 PMCID: PMC5945510 DOI: 10.18632/oncotarget.24944] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 02/27/2018] [Indexed: 12/12/2022] Open
Abstract
Lenalidomide is a potent anti-myeloma drug with immunomodulatory properties. It is increasingly used in a low-dose maintenance setting to prolong remission duration after standard treatment. Data on the in vivo effects of lenalidomide are scarce and sometimes different from the well-described in vitro effects. We therefore evaluated the numerical, phenotypical and functional impact of lenalidomide maintenance on several immune cell types in a cohort of seventeen homogeneously treated myeloma patients achieving a low residual myeloma burden after a bortezomib based-induction followed by autologous stem cell transplantation. Lenalidomide maintenance: 1) increased the fraction of naïve CD8+ T cells and several memory T-cell subsets, 2) reduced the numbers of terminal effector CD8+ T cells, 3) resulted in a higher expression of co-stimulatory molecules on resting T cells and of the inhibitory checkpoint molecules LAG-3 on CD4+ T cells and TIM-3 on CD4+ and CD8+ T cells, 4) reduced the number of TIGIT+ CD8+ T cells, 5) increased the number of regulatory T cells with a phenotype associated with strong suppressive capacity. Purified CD8+ T cells showed increased and more polyfunctional recall viral responses. However, PBMC responses were not enhanced during lenalidomide maintenance and CD4+ T-cell responses specific for the myeloma-associated antigen MAGE-C1 even tended to become lower. We conclude that lenalidomide maintenance after autologous stem cell transplantation has complex pleotropic effects on the immune environment. Immune interventions such as anti-myeloma vaccination should include measures to tackle an expanded inhibitory Treg compartment.
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Affiliation(s)
- Karel Fostier
- Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Hematology, Brussels, Belgium
| | - Jo Caers
- Centre Hospitalier Universitaire (CHU) de Liège, Department of Hematology, Liège, Belgium
| | | | - Katrijn Broos
- Vrije Universiteit Brussel (VUB), Laboratory of Molecular and Cellular Therapy, Brussels, Belgium
| | - Jurgen Corthals
- Vrije Universiteit Brussel (VUB), Laboratory of Molecular and Cellular Therapy, Brussels, Belgium
| | - Kris Thielemans
- Vrije Universiteit Brussel (VUB), Laboratory of Molecular and Cellular Therapy, Brussels, Belgium
| | - Rik Schots
- Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Hematology, Brussels, Belgium
| | - Brenda De Keersmaecker
- Vrije Universiteit Brussel (VUB), Laboratory of Molecular and Cellular Therapy, Brussels, Belgium
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Offidani M, Corvatta L. A review discussing elotuzumab and its use in the second-line plus treatment of multiple myeloma. Future Oncol 2017; 14:319-329. [PMID: 29091475 DOI: 10.2217/fon-2017-0371] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Monoclonal antibodies (mAb) represent a new frontier to treat newly diagnosed and relapsed-refractory multiple myeloma (MM). Elotuzumab, an mAb targeted SLAM7 in the plasma cells and natural killer cells surface, is the first mAb approved for the treatment of relapsed-refractory MM in combination with lenalidomide and dexamethasone. This approval was the final result of several preclinical and Phase I-II clinical studies leading to ELOQUENT-2 Phase III trial that demonstrated that elotuzumab adds a significant and durable value to standard therapy, paved the way of this new treatment strategy for MM. In this review we will describe elotuzumab mechanisms of action, clinical pharmacology and clinical studies that have led to these developments.
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Affiliation(s)
- Massimo Offidani
- Clinica di Ematologia Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
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29
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Wang Q, Lu Y, Li R, Jiang Y, Zheng Y, Qian J, Bi E, Zheng C, Hou J, Wang S, Yi Q. Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma. Leukemia 2017. [PMID: 28626216 DOI: 10.1038/leu.2017.193] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Our previous studies showed that macrophages (MФs), especially myeloma-associated MФs (MAMs), induce chemoresistance in human myeloma. Here we explored the potential of targeting MФs, by using colony-stimulating factor 1 receptor (CSF1R)-blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MФs and MAMs, and repolarized MAMs towards M1-like MФs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4+ T-cell response. Similarly, genetically depleting MФs in myeloma-bearing MMDTR mice retarded myeloma growth in vivo. Furthermore, the combination of CSF1R blockade and chemotherapy such as bortezomib or melphalan displayed an additive therapeutic efficacy against established myeloma. Finally, a fully human CSF1R blocking mAb, similar to its murine counterpart, was able to inhibit the differentiation, proliferation and survival of human MФs. Thus, this study provides the first direct in vivo evidence that MΦs and MAMs are indeed important for myeloma development and progression. Our results also suggest that targeting MAMs by CSF1R blocking mAbs may be promising methods to (re)sensitize myeloma cells to chemotherapy and promote anti-myeloma immune responses in patients.
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Affiliation(s)
- Q Wang
- Department of Cancer Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.,Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Y Lu
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - R Li
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Hematology, The MM and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - Y Jiang
- Department of Cancer Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Y Zheng
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Hematology, and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, Chengdu, China
| | - J Qian
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - E Bi
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - C Zheng
- Department of Hematology, Second Hospital of Shandong University, Jinan, China
| | - J Hou
- Department of Hematology, The MM and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - S Wang
- Department of Cancer Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Q Yi
- Department of Cancer Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.,Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
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Rodríguez-Otero P, Paiva B, Engelhardt M, Prósper F, San Miguel JF. Is immunotherapy here to stay in multiple myeloma? Haematologica 2017; 102:423-432. [PMID: 28082344 PMCID: PMC5394971 DOI: 10.3324/haematol.2016.152504] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/17/2016] [Indexed: 12/28/2022] Open
Abstract
Immune escape and impaired immune surveillance have been identified as emerging hallmarks of cancer.1 Multiple myeloma represents a genuine example of disrupted immune surveillance characterized by: impaired antibody production, deregulation of the T and natural killer cell compartment, disruption of antigen presentation machinery, upregulation of inhibitory surface ligands, and recruitment of immunosuppressive cells. Although the potential value of immunotherapeutic interventions had a clear antecedent in the graft-versus-myeloma effect induced by allogeneic stem cell transplant and donor lymphocyte infusions, it is only recently that this field has faced a real revolution. In this review we discuss the current results obtained with immune approaches in patients with multiple myeloma that have placed this disease under the scope of immuno-oncology, bringing new therapeutic opportunities for the treatment of multiple myeloma patients.
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Affiliation(s)
- Paula Rodríguez-Otero
- Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Bruno Paiva
- Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Monika Engelhardt
- Department of Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, Germany
| | - Felipe Prósper
- Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Jesús F San Miguel
- Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
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Lee SE, Lim JY, Ryu DB, Kim TW, Yoon JH, Cho BS, Eom KS, Kim YJ, Kim HJ, Lee S, Cho SG, Kim DW, Lee JW, Min WS, Kim M, Min CK. Circulating immune cell phenotype can predict the outcome of lenalidomide plus low-dose dexamethasone treatment in patients with refractory/relapsed multiple myeloma. Cancer Immunol Immunother 2016; 65:983-94. [PMID: 27342591 PMCID: PMC11029332 DOI: 10.1007/s00262-016-1861-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 06/15/2016] [Indexed: 12/19/2022]
Abstract
Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3(+), CD4(+), and CD8(+) cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8(+) cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3(+)/CD56(+)) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3(+) cells and CD8(+) cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM.
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Affiliation(s)
- Sung-Eun Lee
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
| | - Ji-Young Lim
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
| | - Da-Bin Ryu
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
| | - Tae Woo Kim
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
| | - Jae-Ho Yoon
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
| | - Byung-Sik Cho
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
- Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea
| | - Ki-Seong Eom
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
- Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea
| | - Yoo-Jin Kim
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
- Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea
| | - Hee-Je Kim
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
- Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea
| | - Seok Lee
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
- Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea
| | - Seok-Goo Cho
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
| | - Dong-Wook Kim
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
- Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea
| | - Jong-Wook Lee
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
| | - Woo-Sung Min
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea
| | - Myungshin Kim
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang-Ki Min
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.
- Catholic Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea.
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Interleukin-16 polymorphisms as new promising biomarkers for risk of gastric cancer. Tumour Biol 2015; 37:2119-26. [PMID: 26346169 DOI: 10.1007/s13277-015-4013-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Accepted: 08/28/2015] [Indexed: 12/27/2022] Open
Abstract
Gastric cancer (GC) is the second cause of cancer-related death worldwide. Interleukin (IL)-16 has a vital role in the development and homeostasis of the immune system. In the present study, we evaluated an exon variant rs4072111 C/T polymorphism and 3' UTR variant rs1131445 C/T within the miRNA binding with gastric cancer susceptibility in Iranian population. Genomic DNA was isolated from peripheral blood samples according to phenol chloroform extraction. The genotypes of IL-16 polymorphisms rs1131445 T/C and rs4072111 T/C were determined by polymerase chain reaction-restriction fragment length polymorphism method. In this case control study, a total of 256 patients with gastric cancer (238 cases (92.9 %) non-cardia and 18 cases (7.1 %) cardia) and 300 healthy control subjects were evaluated. In the present study, we found a significant association between rs4072111 of IL-16 gene and risk of GC in Iranian population. Individuals with CT genotype showed a significant association with 1.79-fold increased risk of GC (P = 0.008; adjusted OR 1.792; 95 % CI 1.164-2.759). The significant association was also detected for T allele of rs4072111 and increased risk of GC (P < 0.001; adjusted OR 1.981; 95 % CI 1.354-2.900). We also observed statistically a significant relationship between rs1131445 of IL-16 CT genotype and GC risk. Carriers of IL-16 CT genotype compared with TT genotype had 1.44 times higher increased likelihood of GC (P = 0.048; adjusted OR 1.445; 95 % CI 1.003-2.084). After stratification according to gender, we observed that in rs1131445, CT and CC male carriers had a higher risk of GC than females (P = 0.08; adjusted OR 1.608; 95 % CI 0.945-2.737 and P = 0.08; adjusted OR 2.186; 95 % CI 0.897-5.325, respectively). We also observed that for male carriers with C allele in rs1131445, there was a 1.53-fold higher risk of GC risk than female subjects (P = 0.029; adjusted OR 1.53; 95 % CI 1.04.4-2.248). We found that the rs1131445 T/C and rs4072111 T/C variants of IL-16 were significantly associated with increased risk of GC in Iranian population.
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Dosani T, Carlsten M, Maric I, Landgren O. The cellular immune system in myelomagenesis: NK cells and T cells in the development of myeloma [corrected] and their uses in immunotherapies. Blood Cancer J 2015; 5:e306. [PMID: 25885426 PMCID: PMC4450330 DOI: 10.1038/bcj.2015.32] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 12/01/2014] [Indexed: 12/28/2022] Open
Abstract
As vast strides are being made in the management and treatment of multiple myeloma (MM), recent interests are increasingly focusing on understanding the development of the disease. The knowledge that MM develops exclusively from a protracted phase of monoclonal gammopathy of undetermined significance provides an opportunity to study tumor evolution in this process. Although the immune system has been implicated in the development of MM, the scientific literature on the role and status of various immune components in this process is broad and sometimes contradictory. Accordingly, we present a review of cellular immune subsets in myelomagenesis. We summarize the current literature on the quantitative and functional profiles of natural killer cells and T-cells, including conventional T-cells, natural killer T-cells, γδ T-cells and regulatory T-cells, in myelomagenesis. Our goal is to provide an overview of the status and function of these immune cells in both the peripheral blood and the bone marrow during myelomagenesis. This provides a better understanding of the nature of the immune system in tumor evolution, the knowledge of which is especially significant considering that immunotherapies are increasingly being explored in the treatment of both MM and its precursor conditions.
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Affiliation(s)
- T Dosani
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - M Carlsten
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - I Maric
- Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - O Landgren
- Myeloma Service, Division of Hematology Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Luo QS, Wang JL, Deng YY, Huang HD, Fu HD, Li CY, Huang HN. Interleukin-16 polymorphism is associated with an increased risk of glioma. Genet Test Mol Biomarkers 2014; 18:711-4. [PMID: 25166752 DOI: 10.1089/gtmb.2014.0170] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE Previous studies have shown that interleukin (IL)-16 is overexpressed in human and rat gliomas. Potential links between IL-16 polymorphisms and glioma risk are currently unclear. The aim of this study was to investigate the association between IL-16 polymorphisms and glioma risk. METHODS We examined IL-16 gene polymorphisms (i.e., rs 4778889, rs 11556218, and rs 4072111) in 216 patients with glioma and 275 controls in a Chinese population. Genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were used to evaluate the effect of the IL-16 polymorphisms on glioma risk. RESULTS The rs 11556218TG genotype is associated with an increased risk of glioma compared with the TT genotype (OR=1.76; 95% CI, 1.22-2.54; p=0.002). Similarly, the rs 11556218G allele is associated with an increased risk of glioma compared with the T allele (OR=1.41; 95% CI, 1.06-1.87; p=0.017). However, no significant association was observed between the IL-16 rs 4778889 and rs 4072111 polymorphisms and the risk of glioma. CONCLUSION These findings suggest that the IL-16 rs 11556218 polymorphism may be used as a susceptibility marker for glioma.
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Affiliation(s)
- Qi-Sheng Luo
- 1 Department of Neurosurgery, Affiliated Hospital of Youjiang Medical College for Nationalities , Guangxi, Baise, People's Republic of China
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35
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Nischwitz S, Faber H, Sämann PG, Domingues HS, Krishnamoorthy G, Knop M, Müller-Sarnowski F, Yassouridis A, Weber F. Interferon β-1a reduces increased interleukin-16 levels in multiple sclerosis patients. Acta Neurol Scand 2014; 130:46-52. [PMID: 24571587 DOI: 10.1111/ane.12215] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2013] [Indexed: 12/14/2022]
Abstract
OBJECTIVES There is convergent evidence for an important role of interleukin-16 (IL-16) in the pathogenesis of multiple sclerosis (MS). IL-16 serves as a chemoattractant for different immune cells that are involved in developing lesions. Here, we compared IL-16 levels of MS patients and controls and addressed the long-term effect of IFN-β, the most common immunomodulatory MS therapy, on IL-16 serum levels in MS patients over 2 years. Beyond this, we analysed the expression of IL-16 in two CD4(+) T-cell subsets, Th1 and Th17 cells, which are important autoimmune mediators and affected by IFN-β treatment, derived from myelin-specific T-cell transgenic mice. MATERIALS AND METHODS IL-16 serum levels of 17 controls and of 16 MS patients before therapy and at months 1, 2, 3, 6, 9, 12 and 24 during IFN-β1a therapy were determined by ELISA. MRI was performed before therapy, at months 12 and 24. IL-16 expression of in vitro differentiated murine myelin oligodendrocyte glycoprotein (MOG)-specific Th1 and Th17 cells was quantified by real-time PCR. RESULTS Before therapy, MS patients showed significantly elevated IL-16 levels compared with controls irrespective of disease activity determined by MRI. Therapy with IFN-β1a led to a significant linear decrease in IL-16 serum levels beginning after 2 months. MOG-specific Th17 cells expressed more IL-16 than Th1 cells. CONCLUSIONS Reduction in increased IL-16 levels may be of relevance for the therapeutic effect of IFN-β1a in MS. Easily accessible IL-16 serum levels hold a potential as biomarker of treatment efficacy in MS.
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Affiliation(s)
- S. Nischwitz
- RG Inflammatory Disorders of the CNS, Neurology; Max Planck Institute of Psychiatry; Munich Germany
| | - H. Faber
- RG Inflammatory Disorders of the CNS, Neurology; Max Planck Institute of Psychiatry; Munich Germany
| | - P. G. Sämann
- RG Neuroimaging; Max Planck Institute of Psychiatry; Munich Germany
| | - H. S. Domingues
- Max Planck Institute of Neurobiology; Martinsried Germany
- Instituto de Biologia Molecular e Celular R. Campo Alegre; Porto Portugal
| | | | - M. Knop
- RG Inflammatory Disorders of the CNS, Neurology; Max Planck Institute of Psychiatry; Munich Germany
| | - F. Müller-Sarnowski
- RG Inflammatory Disorders of the CNS, Neurology; Max Planck Institute of Psychiatry; Munich Germany
| | - A. Yassouridis
- RG Biostatistics; Max Planck Institute of Psychiatry; Munich Germany
| | - F. Weber
- RG Inflammatory Disorders of the CNS, Neurology; Max Planck Institute of Psychiatry; Munich Germany
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Richmond J, Tuzova M, Cruikshank W, Center D. Regulation of cellular processes by interleukin-16 in homeostasis and cancer. J Cell Physiol 2013; 229:139-47. [PMID: 23893766 DOI: 10.1002/jcp.24441] [Citation(s) in RCA: 124] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 07/22/2013] [Indexed: 12/21/2022]
Abstract
Interleukin-16 (IL-16) is generated as a precursor molecule that is cleaved by caspase-3 to produce a pro-IL-16 molecule that functions as a regulator of T cell growth, and a secreted peptide that functions as a CD4 and/or CD9 ligand for induction of cell motility and activation. IL-16 has been predominantly studied as a contributing factor in the orchestration of an immune response; however, more recently IL-16 bioactivity has been closely associated with the progression of a number of different cancers. While the association between IL-16 plasma levels and tumor progression has been reported for many types of cancer, the mechanism for IL-16 involvement has been partially elucidated for three of the cancer types, cutaneous T cell lymphoma (CTCL), multiple myeloma (MM), and breast cancer. The mechanism for promoting cell growth is different in each of these cancers and involves a sequence mutation in the pro-molecule facilitating decreased p27(KIP1) levels in CTCL; over expression of the secreted IL-16 molecule to induce proliferation in CTCL T cells, and plasma cells in MM; and increased secreted IL-16 acting to recruit CD4+ pro-tumor macrophages in breast cancer. This article will review the cellular process for generating IL-16, the biological activities for both the pro- and secreted forms of the protein, and then the mechanism by which these forms contribute to cancer progression. As a soluble cytokine the ability to reduce or eliminate IL-16 synthesis through siRNA approaches or bioactivity through the use of neutralizing antibody treatment may represent a novel therapeutic approach.
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Affiliation(s)
- Jillian Richmond
- Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts
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Qin X, Peng Q, Lao X, Chen Z, Lu Y, Lao X, Mo C, Sui J, Wu J, Zhai L, Yang S, Li S, Zhao J. The association of interleukin-16 gene polymorphisms with IL-16 serum levels and risk of nasopharyngeal carcinoma in a Chinese population. Tumour Biol 2013; 35:1917-24. [PMID: 24101193 DOI: 10.1007/s13277-013-1257-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 09/25/2013] [Indexed: 02/06/2023] Open
Abstract
Interleukin (IL)-16 plays a fundamental role in inflammatory diseases, as well as in the development and progression of tumors. Genetic variation in DNA sequence of IL16 gene may lead to altered cytokine production and/or activity, and this variation may modulate an individual's susceptibility to nasopharyngeal carcinoma (NPC). To test this hypothesis, we investigated the association of IL16 gene polymorphisms and serum IL-16 levels with NPC risk in a Chinese population. We analyzed IL16 gene rs11556218 T/G, rs4778889 T/C, and rs4072111 C/T polymorphisms using PCR-RFLP and DNA sequencing, and serum IL-16 levels were measured by ELISA. The IL16 rs11556218 T/G polymorphism was significantly associated with the susceptibility to NPC patients. The TG genotype was associated with a significantly higher risk of NPC as compared with the TT genotype (OR = 2.05, 95% CI 1.04-4.01; p = 0.037). Patients carrying the G allele had a significantly higher risk for developing NPC compared with individuals carrying the T allele (OR = 1.79, 95% CI 1.07-3.01; p = 0.027). The serum IL-16 levels were increased in NPC patients compared with controls (p < 0.01); the genotypes carrying the IL16 rs11556218 G variant allele were associated with increased serum IL-16 levels compared with the homozygous wild-type genotype in NPC patients (all p values <0.01). Our data suggested that IL16 rs11556218 T/G polymorphism was associated with increased susceptibility to NPC through increasing the production of serum IL-16 levels.
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Affiliation(s)
- Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
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Maranville JC, Baxter SS, Witonsky DB, Chase MA, Di Rienzo A. Genetic mapping with multiple levels of phenotypic information reveals determinants of lymphocyte glucocorticoid sensitivity. Am J Hum Genet 2013; 93:735-43. [PMID: 24055111 DOI: 10.1016/j.ajhg.2013.08.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 07/12/2013] [Accepted: 08/01/2013] [Indexed: 12/13/2022] Open
Abstract
Clinical response to glucocorticoids, steroid hormones widely used as pharmaceuticals, varies extensively in that many individuals (∼30%) show a weak response to treatment. Although little is known about the molecular basis of this variation, regulatory polymorphisms are likely to play a key role given that glucocorticoids act largely through activation of a transcription factor, the glucocorticoid receptor. In an effort to characterize the molecular basis of variation in glucocorticoid sensitivity, we measured in vitro lymphocyte glucocorticoid sensitivity and transcriptome-wide response to glucocorticoids in peripheral-blood mononuclear cells from African American healthy donors. We found that variation in lymphocyte glucocorticoid sensitivity was correlated with transcriptional response at 27 genes (false-discovery rate < 0.1). Furthermore, a genome-wide association scan revealed a quantitative trait locus (QTL) for lymphocyte glucocorticoid sensitivity (rs11129354, p = 4 × 10(-8)); it was also associated with transcriptional response at multiple genes, including many (14/27) where transcriptional response was correlated with lymphocyte glucocorticoid sensitivity. Using allelic-imbalance assays, we show that this QTL is a glucocorticoid-dependent cis-regulatory polymorphism for RBMS3, which encodes an RNA-binding protein known as a tumor suppressor. We found that siRNA-mediated knockdown of RBMS3 expression increased cellular proliferation in PBMCs, consistent with the role of the gene as a negative regulator of proliferation. We propose that differences in lymphocyte glucocorticoid sensitivity reflect variation in transcriptional response, which is influenced by a glucocorticoid-dependent regulatory polymorphism that acts in cis relative to RBMS3 and in trans to affect the transcriptional response of multiple distant genes.
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Affiliation(s)
- Joseph C Maranville
- Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, 900 East 57(th) Street, Chicago, IL 60637, USA; Department of Human Genetics, The University of Chicago, 920 East 58(th) Street, Chicago, IL 60637, USA
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39
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Milke L, Schulz K, Weigert A, Sha W, Schmid T, Brüne B. Depletion of tristetraprolin in breast cancer cells increases interleukin-16 expression and promotes tumor infiltration with monocytes/macrophages. Carcinogenesis 2012; 34:850-7. [PMID: 23241166 DOI: 10.1093/carcin/bgs387] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The RNA-binding protein tristetraprolin (TTP) destabilizes target messenger RNAs (mRNAs) containing AU-rich elements within their 3' untranslated region. Thereby, it controls the expression of multiple inflammatory and tumor-associated transcripts. Moreover, a loss of TTP in tumors predicts disease-associated survival. Although tumor intrinsic functions of TTP have previously been studied, the impact of TTP on the interaction of tumors with their microenvironment remains elusive. As immune cell infiltration into tumors is a critical determinant for tumor progression, this study aimed at determining the influence of tumor cell TTP on the interaction between tumor and immune cells, specifically monocytes (MO)/macrophages (MΦ). Knockdown (k/d) of TTP in T47D breast cancer cells enhanced tumor growth both in vitro and in vivo and increased infiltration of MO into 3D tumor spheroids in vitro and of MΦ into tumor xenografts in vivo. Enhanced migration of MO toward supernatants of TTP-deficient tumor spheroids was determined as the underlying principle. Interestingly, we noticed interleukin-16 (IL-16) mRNA stabilization when TTP was depleted. In line, IL-16 protein levels were elevated in TTP-deficient spheroids and their supernatants as well as in TTP k/d tumor xenografts and critically contributed to the enhanced chemotactic behavior. In summary, we show that the loss of TTP in tumors not only affects tumor cell proliferation and survival but also enhances infiltration of MO/MΦ into the tumors, which is typically associated with poor prognosis. Moreover, we identified IL-16 as a critical TTP-regulated chemotactic factor that contributes to MO/MΦ migration.
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Affiliation(s)
- Larissa Milke
- Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
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Atanackovic D, Hildebrandt Y, Templin J, Cao Y, Keller C, Panse J, Meyer S, Reinhard H, Bartels K, Lajmi N, Sezer O, Zander AR, Marx AH, Uhlig R, Zustin J, Bokemeyer C, Kroger N. Role of Interleukin 16 in Multiple Myeloma. J Natl Cancer Inst 2012; 104:1005-20. [DOI: 10.1093/jnci/djs257] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Jöhrer K, Hofbauer SW, Zelle-Rieser C, Greil R, Hartmann TN. Chemokine-dependent B cell-T cell interactions in chronic lymphocytic leukemia and multiple myeloma - targets for therapeutic intervention? Expert Opin Biol Ther 2012; 12:425-41. [PMID: 22332909 DOI: 10.1517/14712598.2012.664128] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Chemokines and their receptors play essential roles in the development, maintenance and proper functioning of the immune system. B cell-T cell interactions are modulated by chemokines. In B cell malignancies, these interactions may have tumor-promoting consequences. AREAS COVERED This review summarizes physiological B cell-T cell interactions and discusses their pathological role in the onset and progression of B cell malignancies with a special focus on chronic lymphocytic leukemia and multiple myeloma. Experimental data on chemokine-guided B cell-T cell actions in B cell malignancies from murine models as well as in vitro data are summarized and their potential as future therapeutic targets is critically discussed. EXPERT OPINION Direct or indirect targeting of chemokine receptors involved in localization and T-cell-dependent activation of B lymphocytes can provide strong synergisms with conventional or immunomodulatory therapies by disrupting the microenvironmental conditions necessary for survival and proliferation of malignant B lymphocytes. However, further knowledge of these interactions between B and T cells is needed.
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Affiliation(s)
- Karin Jöhrer
- Tyrolean Cancer Research Institute, Innsbruck, Austria.
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Impacts of heat stress on baseline immune measures and a subset of T cells in Bama miniature pigs. Livest Sci 2011. [DOI: 10.1016/j.livsci.2010.07.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Transfer of influenza vaccine-primed costimulated autologous T cells after stem cell transplantation for multiple myeloma leads to reconstitution of influenza immunity: results of a randomized clinical trial. Blood 2010; 117:63-71. [PMID: 20864577 DOI: 10.1182/blood-2010-07-296822] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Severe immune deficiency follows autologous stem cell transplantation for multiple myeloma and is associated with significant infectious morbidity. This study was designed to evaluate the utility of a pretransplantation vaccine and infusion of a primed autologous T-cell product in stimulating specific immunity to influenza. Twenty-one patients with multiple myeloma were enrolled from 2007 to 2009. Patients were randomly assigned to receive an influenza-primed autologous T-cell product or a nonspecifically primed autologous T-cell product. The study endpoint was the development of hemagglutination inhibition titers to the strain-specific serotypes in the influenza vaccine. Enzyme-linked immunospot assays were performed to confirm the development of influenza-specific B-cell and T-cell immunity. Patients who received the influenza-primed autologous T-cell product were significantly more likely to seroconvert in response to the influenza vaccine (P = .001). Seroconversion was accompanied by a significant B-cell response. No differences were observed in the global quantitative recovery of T-cell and B-cell subsets or in global T-cell and B-cell function. The provision of a primed autologous T-cell product significantly improved subsequent influenza vaccine responses. This trial was registered at www.clinicaltrials.gov as #NCT00499577.
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Deng Q, Xu J, Yu B, He J, Zhang K, Ding X, Chen D. Effect of dietary tea polyphenols on growth performance and cell-mediated immune response of post-weaning piglets under oxidative stress. Arch Anim Nutr 2010; 64:12-21. [PMID: 20496858 DOI: 10.1080/17450390903169138] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
To gain insights into the effects of tea polyphenols (TP) on growth performance and cell-mediated immune response of piglets under oxidative stress, an oxidative stress model was established by intraperitoneally injecting weaned piglets with diquat. After intake of either basal diet or TP-supplemented diet for 7 d, half of the piglets in each group were challenged with diquat. Results showed that dietary TP alleviated growth depression to some extent. A T lymphocyte transformation test (LTT) demonstrated that TP promoted the proliferation and activation of T lymphocytes. The ratio of CD4+/CD8+ was elevated, indicating a recovering tendency from immune damages caused by oxidative stress. The increment of pro-inflammatory IL-1 caused by oxidative stress was attenuated, and the concentration of serum IFN-gamma was decreased by TP-supplementation. However, the serum concentrations of anti-inflammatory cytokine, such as IL-4, were greatly enhanced by TP, which suggested an immune shift from Th1 to Th2. These findings supported the immunomodulatory potential of TP for piglets subjected to oxidative stress.
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Affiliation(s)
- Qilan Deng
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Ya'an, Sichuan, P.R. China
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Berard JL, Wolak K, Fournier S, David S. Characterization of relapsing-remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice. Glia 2010; 58:434-45. [PMID: 19780195 DOI: 10.1002/glia.20935] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Like MS, the animal model experimental autoimmune encephalomyelitis (EAE) is characterized by CNS inflammation and demyelination and can follow a relapsing-remitting (RR) or chronic (CH) disease course. The molecular and pathological differences that underlie these different forms of EAE are not fully understood. We have compared the differences in RR- and CH-EAE generated in the same mouse strain (C57BL/6) using the same antigen. At the peak of disease when mice in both groups have similar clinical scores, CH-EAE is associated with increased lesion burden, myelin loss, axonal damage, and chemokine/cytokine expression when compared with RR-EAE. We further showed that inflammation and myelin loss continue to worsen in later stages of CH-EAE, whereas these features are largely resolved at the equivalent stage in RR-EAE. Additionally, axonal loss at these later stages is more severe in CH-EAE than in RR-EAE. We also demonstrated that CH-EAE is associated with a greater predominance of CD8(+) T cells in the CNS that exhibit MOG(35-55) antigen specificity. These studies therefore showed that, as early as the peak stage of disease, RR- and CH-EAE differ remarkably in their immune cell profile, chemokine/cytokine responses, and histopathological features. These data also indicated that this model of CH-EAE exhibits pathological features of a chronic-progressive disease profile and suggested that the sustained chronic phenotype is due to a combination of axonal loss, myelin loss, and continuing inflammation.
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Affiliation(s)
- Jennifer L Berard
- Center for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
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Gao LB, Liang WB, Xue H, Rao L, Pan XM, Lv ML, Bai P, Fang WL, Liu J, Liao M, Zhang L. Genetic polymorphism of interleukin-16 and risk of nasopharyngeal carcinoma. Clin Chim Acta 2009; 409:132-5. [PMID: 19758567 DOI: 10.1016/j.cca.2009.09.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2009] [Revised: 09/09/2009] [Accepted: 09/09/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND Common genetic variants in inflammatory cytokine genes can affect the risk of developing nasopharyngeal carcinoma (NPC). Interleukin-16 (IL-16), a pro-inflammatory cytokine, plays a pivotal role in inflammatory diseases as well as in the pathogenesis of tumors. METHODS We analyzed rs4778889 T/C, rs11556218 T/G, and rs4072111 C/T polymorphisms of IL-16 in 206 patients with NPC and 373 healthy controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy and DNA sequencing methods. RESULTS The rs11556218 T/G polymorphism of IL-16 gene was significantly associated with the susceptibility to NPC. The TG genotype was associated with a significantly higher risk of NPC as compared with the TT genotype (OR=1.67; 95% CI, 1.18-2.36). Patients carrying the G allele had a significantly higher risk for developing NPC compared to individuals carrying the T allele (OR=1.36; 95% CI, 1.03-1.78). CONCLUSIONS This study shows an association between IL-16 gene polymorphisms and the risk of NPC, and our data suggests that IL-16 gene polymorphisms may be useful as genetic susceptibility markers for NPC.
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Affiliation(s)
- Lin-Bo Gao
- Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
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Bellomo G, Allegra A, Alonci A, Quartarone E, Pizzoleo MA, Cincotta M, Del Fabro V, Guglielmo S, Musolino C. Serum levels of interleukin-16 in lymphoid malignancies. Leuk Lymphoma 2009; 48:1225-7. [PMID: 17577790 DOI: 10.1080/10428190701268767] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Gao LB, Rao L, Wang YY, Liang WB, Li C, Xue H, Zhou B, Sun H, Li Y, Lv ML, Du XJ, Zhang L. The association of interleukin-16 polymorphisms with IL-16 serum levels and risk of colorectal and gastric cancer. Carcinogenesis 2008; 30:295-9. [PMID: 19073878 DOI: 10.1093/carcin/bgn281] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Interleukin (IL)-16, a multifunctional cytokine, plays a fundamental role in inflammatory diseases, as well as in the development and progression of tumors. Genetic variation in the DNA sequence of the IL-16 gene may lead to altered cytokine production and/or activity, and this variation may modulate an individual's susceptibility to both colorectal cancer (CRC) and gastric cancer (GC). To test this hypothesis, we investigated the association of IL-16 gene polymorphisms with serum levels of IL-16 and the risk of CRC and GC in a Chinese population. We analyzed single-nucleotide polymorphisms of the IL-16 gene in 596 cancer patients (376 patients with CRC and 220 patients with GC), and also in 480 age- and sex-matched controls using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Serum IL-16 levels were measured by enzyme-linked immunosorbent assay. The rs11556218 T/G polymorphism of the IL-16 gene was significantly associated with the susceptibility to CRC and GC patients. Both male and female patients carrying the G allele had a significantly higher risk for developing CRC and GC compared with individuals carrying the T allele. Alternatively, women carrying the T allele (rs4072111 C/T) showed a decreased risk for CRC and GC compared with individuals carrying the C allele. In patients with CRC or GC, IL-16 serum levels were significantly higher than those in the healthy controls, although no significant association between IL-16 polymorphisms and serum levels of IL-16 was observed. Our data indicate that IL-16 polymorphisms may contribute to CRC and GC susceptibility.
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Affiliation(s)
- Lin-Bo Gao
- Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, People's Republic of China
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Laronne-Bar-On A, Zipori D, Haran-Ghera N. Increased regulatory versus effector T cell development is associated with thymus atrophy in mouse models of multiple myeloma. THE JOURNAL OF IMMUNOLOGY 2008; 181:3714-24. [PMID: 18714048 DOI: 10.4049/jimmunol.181.5.3714] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play a central role in cancer tolerance. However, mechanisms leading to their accumulation in cancer remain unknown. Although the thymus is the main site of Treg development, thymic contribution to Treg expansion in cancer has not been directly examined. Herein, we used two murine models of multiple myeloma (MM), 5T2 MM and 5T33 MM, to examine Treg accumulation in peripheral lymphoid organs, including spleen, lymph nodes, bone marrow, and blood, and to explore thymic Treg development during malignancy. We found that peripheral ratios of suppressive-functional Tregs increased in both models of MM-inflicted mice. We found that thymic ratios of Treg development in MM increased, in strong association with thymus atrophy and altered developmental processes in the thymus. The CD4(+)CD8(+) double-positive population, normally the largest thymocyte subset, is significantly decreased, whereas the CD4(-)CD8(-) double-negative population is increased. Administration of thymocytes from MM-inflicted mice compared with control thymocytes resulted in increased progression of the disease, and this effect was shown to be mediated by Tregs in the thymus of MM-inflicted mice. Our data suggest that increased ratios of Treg development in the thymus may contribute to disease progression in MM-inflicted mice.
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Affiliation(s)
- Ayelet Laronne-Bar-On
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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Passam FH, Sfiridaki A, Pappa C, Kyriakou D, Petreli E, Roussou PA, Alexandrakis MG. Angiogenesis-related growth factors and cytokines in the serum of patients with B non-Hodgkin lymphoma; relation to clinical features and response to treatment. Int J Lab Hematol 2008; 30:17-25. [PMID: 18190463 DOI: 10.1111/j.1365-2257.2006.00890.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Increased angiogenesis has been shown to be a feature of non-Hodgkin lymphomas (NHL). In the current study, the pretreatment levels of circulating molecules related to angiogenesis were determined in 49 B-cell NHL patients and correlated with histological grade, disease stage and prognostic score. In 25 patients, the same molecules were defined after standard treatment. Vascular endothelial growth factor (VEGF), angiogenin, interleukin-2 (IL-2), IL-6, IL-8 and IL-16 were measured. Increased levels of VEGF, IL-6 and IL-8 were found in the whole group of untreated patients in comparison with normal controls (P < 0.05), whereas, IL-2 was higher in the subgroup of indolent NHL. Overall, there was no significant decrease in the levels of these molecules after treatment. However, by stratification into group of responders vs. non-responders pretreatment IL-8 was significantly increased whereas IL-16 was decreased in the subgroup of complete responders. According to the REAL classification IL-2 was higher in the low risk compared with intermediate plus high-risk group. There was no association with disease stage or the International Prognostic Score. Both indolent and aggressive B cell lymphomas have increased production of angiogenic mediators and cytokines with IL-8 and IL-16 potentially reflecting the response to treatment.
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Affiliation(s)
- F H Passam
- III Department of Internal Medicine, Sotiria Hospital, Medical School of Athens, University of Athens, Athens, Greece.
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