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1
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Chandora K, Chandora A, Saeed A, Cavalcante L. Adoptive T Cell Therapy Targeting MAGE-A4. Cancers (Basel) 2025; 17:413. [PMID: 39941782 PMCID: PMC11815873 DOI: 10.3390/cancers17030413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/20/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
MAGE A4 (Melanoma Antigen Gene A4) is a cancer testis antigen (CTA) that is expressed normally in germline cells (testis/embryonic tissues) but absent in somatic cells. The MAGE A4 CTA is expressed in a variety of tumor types, like synovial sarcoma, ovarian cancer and non-small cell lung cancer. Having its expression profile limited to germline cells has made MAGE A4 a sought-after immunotherapeutic target in certain malignancies. In this review, we focus on MAGE-A4's function and expression, current clinical trials involving targeted immunotherapy approaches, and challenges and opportunities facing MAGE-A4's targeted therapeutics.
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Affiliation(s)
- Kapil Chandora
- Morehouse School of Medicine, 720 Westview Dr, Atlanta, GA 30310, USA; (K.C.)
| | - Akshay Chandora
- Morehouse School of Medicine, 720 Westview Dr, Atlanta, GA 30310, USA; (K.C.)
| | - Anwaar Saeed
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA;
| | - Ludimila Cavalcante
- Division of Hematology and Oncology, University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22903, USA
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2
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Shklovskaya E, Rizos H. MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It. Int J Mol Sci 2021; 22:ijms22136741. [PMID: 34201655 PMCID: PMC8268865 DOI: 10.3390/ijms22136741] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 12/21/2022] Open
Abstract
It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.
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Extracellular Vesicles Mediate B Cell Immune Response and Are a Potential Target for Cancer Therapy. Cells 2020; 9:cells9061518. [PMID: 32580358 PMCID: PMC7349483 DOI: 10.3390/cells9061518] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/18/2020] [Accepted: 06/18/2020] [Indexed: 12/21/2022] Open
Abstract
Extracellular vesicles (EVs) are increasingly understood to participate directly in many essential aspects of host antitumor immune response. Tumor- and immune-cell-derived EVs function in local and systemic contexts with roles in immune processes including cancer antigen conveyance, immune cell priming and activation, as well as immune escape. Current practice of cancer immunotherapy has de facto focused on eliciting T-cell-mediated cytotoxic responses. Humoral immunity is also known to exert antitumor effects, and B cells have been demonstrated to have functions that extend beyond antibody production to include antigen presentation and activation and modulation of T cells and innate immune effectors. Evidence of B cell response against tumor-associated antigens (TAAs) is observed in early stages of tumorigenesis and in most solid tumor types. It is known that EVs convey diverse TAAs, express antigenic-peptide-loaded MHCs, and complex with circulating plasma antitumoral autoantibodies. In this review, we will consider the relationships between EVs, B cells, and other antigen-presenting cells, especially in relation to TAAs. Understanding the intersection of EVs and the cancer immunome will enable opportunities for developing tumor antigen targets, antitumor vaccines and harnessing the full potential of multiple immune system components for next-generation cancer immunotherapies.
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Capello M, Vykoukal JV, Katayama H, Bantis LE, Wang H, Kundnani DL, Aguilar-Bonavides C, Aguilar M, Tripathi SC, Dhillon DS, Momin AA, Peters H, Katz MH, Alvarez H, Bernard V, Ferri-Borgogno S, Brand R, Adler DG, Firpo MA, Mulvihill SJ, Molldrem JJ, Feng Z, Taguchi A, Maitra A, Hanash SM. Exosomes harbor B cell targets in pancreatic adenocarcinoma and exert decoy function against complement-mediated cytotoxicity. Nat Commun 2019; 10:254. [PMID: 30651550 PMCID: PMC6335434 DOI: 10.1038/s41467-018-08109-6] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 12/12/2018] [Indexed: 12/25/2022] Open
Abstract
Although B cell response is frequently found in cancer, there is little evidence that it alters tumor development or progression. The process through which tumor-associated antigens trigger humoral response is not well delineated. We investigate the repertoire of antigens associated with humoral immune response in pancreatic ductal adenocarcinoma (PDAC) using in-depth proteomic profiling of immunoglobulin-bound proteins from PDAC patient plasmas and identify tumor antigens that induce antibody response together with exosome hallmark proteins. Additional profiling of PDAC cell-derived exosomes reveals significant overlap in their protein content with immunoglobulin-bound proteins in PDAC plasmas, and significant autoantibody reactivity is observed between PDAC cell-derived exosomes and patient plasmas compared to healthy controls. Importantly, PDAC-derived exosomes induce a dose-dependent inhibition of PDAC serum-mediated complement-dependent cytotoxicity towards cancer cells. In summary, we provide evidence that exosomes display a large repertoire of tumor antigens that induce autoantibodies and exert a decoy function against complement-mediated cytotoxicity.
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Affiliation(s)
- Michela Capello
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Jody V. Vykoukal
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA ,0000 0001 2291 4776grid.240145.6The McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Hiroyuki Katayama
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Leonidas E. Bantis
- 0000 0001 2291 4776grid.240145.6Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA ,0000 0001 2177 6375grid.412016.0Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Hong Wang
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Deepali L. Kundnani
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Clemente Aguilar-Bonavides
- 0000 0001 2291 4776grid.240145.6Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Mitzi Aguilar
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Satyendra C. Tripathi
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Dilsher S. Dhillon
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Amin A. Momin
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Haley Peters
- 0000 0001 2291 4776grid.240145.6Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Matthew H. Katz
- 0000 0001 2291 4776grid.240145.6Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Hector Alvarez
- 0000 0001 2291 4776grid.240145.6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Vincent Bernard
- 0000 0001 2291 4776grid.240145.6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Sammy Ferri-Borgogno
- 0000 0001 2291 4776grid.240145.6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Randall Brand
- 0000 0004 1936 9000grid.21925.3dDivision of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15232 USA
| | - Douglas G. Adler
- 0000 0001 2193 0096grid.223827.eDepartment of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132 USA
| | - Matthew A. Firpo
- 0000 0001 2193 0096grid.223827.eDepartment of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132 USA
| | - Sean J. Mulvihill
- 0000 0001 2193 0096grid.223827.eDepartment of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132 USA
| | - Jeffrey J. Molldrem
- 0000 0001 2291 4776grid.240145.6Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Ziding Feng
- 0000 0001 2291 4776grid.240145.6Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Ayumu Taguchi
- 0000 0001 2291 4776grid.240145.6Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Anirban Maitra
- 0000 0001 2291 4776grid.240145.6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA ,0000 0001 2291 4776grid.240145.6Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Samir M. Hanash
- 0000 0001 2291 4776grid.240145.6Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA ,0000 0001 2291 4776grid.240145.6The McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA ,0000 0001 2291 4776grid.240145.6Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
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Abstract
The varied landscape of the adaptive immune response is determined by the peptides presented by immune cells, derived from viral or microbial pathogens or cancerous cells. The study of immune biomarkers or antigens is not new, and classical methods such as agglutination, enzyme-linked immunosorbent assay, or Western blotting have been used for many years to study the immune response to vaccination or disease. However, in many of these traditional techniques, protein or peptide identification has often been the bottleneck. Recent progress in genomics and mass spectrometry have led to many of the rapid advances in proteomics approaches. Immunoproteomics describes a rapidly growing collection of approaches that have the common goal of identifying and measuring antigenic peptides or proteins. This includes gel-based, array-based, mass spectrometry-based, DNA-based, or in silico approaches. Immunoproteomics is yielding an understanding of disease and disease progression, vaccine candidates, and biomarkers. This review gives an overview of immunoproteomics and closely related technologies that are used to define the full set of protein antigens targeted by the immune system during disease.
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Affiliation(s)
- Kelly M Fulton
- Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, ON, Canada
| | - Isabel Baltat
- Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, ON, Canada
| | - Susan M Twine
- Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, ON, Canada.
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6
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Rao S, Gharib K, Han A. Cancer Immunosurveillance by T Cells. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 342:149-173. [PMID: 30635090 DOI: 10.1016/bs.ircmb.2018.08.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cancer immunotherapy is based on the ability of the immune system to recognize tumors as foreign tissue. The idea of cancer immunosurveillance was first conceived over a century ago but remained controversial through much of the 20th century. In the past few decades, however, the field has progressed rapidly, and the concept of tumor immunosurveillance is now well established. With this chapter, we provide a historical background of immunosurveillance, the concept of immunoediting, and the role of different T-cell subsets in the tumor microenvironment. We also discuss the relationship between immune checkpoints, tumor antigens, T cell receptor repertoire, and immunosurveillance. Finally, we comment on the future of immunotherapy as it relates to T cell immunosurveillance.
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Affiliation(s)
- Samhita Rao
- Departments of Medicine and Microbiology and Immunology, Columbia Center for Translational Immunology, Columbia University, New York, NY, United States
| | - Karim Gharib
- Departments of Medicine and Microbiology and Immunology, Columbia Center for Translational Immunology, Columbia University, New York, NY, United States
| | - Arnold Han
- Departments of Medicine and Microbiology and Immunology, Columbia Center for Translational Immunology, Columbia University, New York, NY, United States
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7
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Therapeutic cancer vaccines: From initial findings to prospects. Immunol Lett 2018; 196:11-21. [DOI: 10.1016/j.imlet.2018.01.011] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 12/30/2017] [Accepted: 01/24/2018] [Indexed: 12/15/2022]
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Abstract
The question of whether human tumors express antigens that can be recognized by the immune system has been answered with a resounding YES. Most were identified through spontaneous antitumor humoral and cellular immune responses found in cancer patients and include peptides, glycopeptides, phosphopeptides, viral peptides, and peptides resulting from common mutations in oncogenes and tumor-suppressor genes, or common gene fusion events. Many have been extensively tested as candidates for anticancer vaccines. More recently, attention has been focused on the potentially large number of unique tumor antigens, mutated neoantigens, that are the predicted products of the numerous mutations revealed by exome sequencing of primary tumors. Only a few have been confirmed as targets of spontaneous immunity and immunosurveillance, and even fewer have been tested in preclinical and clinical settings. The field has been divided for a long time on the relative importance of shared versus mutated antigens in tumor surveillance and as candidates for vaccines. This question will eventually need to be answered in a head to head comparison in well-designed clinical trials. One advantage that shared antigens have over mutated antigens is their potential to be used in vaccines for primary cancer prevention. Cancer Immunol Res; 5(5); 347-54. ©2017 AACR.
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Affiliation(s)
- Olivera J Finn
- Department of Immunology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
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9
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Chaperonin containing TCP1 subunit 5 is a tumor associated antigen of non-small cell lung cancer. Oncotarget 2017; 8:64170-64179. [PMID: 28969060 PMCID: PMC5609992 DOI: 10.18632/oncotarget.19369] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 06/18/2017] [Indexed: 01/12/2023] Open
Abstract
Novel tumor antigens and their related autoantibodies have tremendous potential for early diagnosis of non-small cell lung cancer (NSCLC). In this study, we identify antigens from NSCLC tissue and autoantibodies in sera of patients with NSCLC using a modified proteomics-based approach. We seperated and identified four NSCLC-associated proteins extracted from the cytosol in tumor tissues by mini-two-dimensional gel electrophoresis, followed by Western blot and hybridization with individual sera for confirmation of antibody binding. Of the proteins we identified, we selected 58 kDa chaperonin containing TCP1(T-Complex Protein 1) subunit 5 (CCT5) for validation. Serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) were measured in all serum samples with an immunoluminometric assay and a receiver operating characteristic (ROC) curve was analyzed for autoantibodies against CCT5, CEA and CYFRA 21-1. The results show that CCT5 can induce an autoantibody response in NSCLC sera and show higher expression in NSCLC tissues by immunohistochemistry and Western blot. Anti-CCT5 autoantibody was found in 51% (23/45) of patients with NSCLC, but only 2.5% (1/40) in non-tumor individual controls. A receiver operating characteristic curve constructed with a panel of autoantibodies against CCT5 (AUC=0.749), CEA (AUC=0.6758), and CYFRA 21-1(AUC=0.760) show a sensitivity of 51.1% and 97.5% specificity in discriminating NSCLC from matched controls. These results indicate the potential utility of screening autoantibodies in sera, show that CCT5 could be used as a biomarker in cancer diagnosis.
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10
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Abstract
Historically, immune-based therapies have played a leading role in the treatment of hematologic malignancies, with the efficacy of stem cell transplantation largely attributable to donor immunity against malignant cells. As new and more targeted immunotherapies have developed, their role in the treatment of hematologic malignancies is evolving and expanding. Herein, we discuss approaches for antigen discovery and review known and novel tumor antigens in hematologic malignancies. We further explore the role of established and investigational immunotherapies in hematologic malignancies, with a focus on personalization of treatment modalities such as cancer vaccines and adoptive cell therapy. Finally, we identify areas of active investigation and development. Immunotherapy is at an exciting crossroads for the treatment of hematologic malignancies, with further investigation aimed at producing effective, targeted immune therapies that maximize antitumor effects while minimizing toxicity.
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Affiliation(s)
- David A. Braun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Catherine J. Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Suri A, Jagadish N, Saini S, Gupta N. Targeting cancer testis antigens for biomarkers and immunotherapy in colorectal cancer: Current status and challenges. World J Gastrointest Oncol 2015; 7:492-502. [PMID: 26691579 PMCID: PMC4678396 DOI: 10.4251/wjgo.v7.i12.492] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 08/07/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer ranks third among the estimated cancer cases and cancer related mortalities in United States in 2014. Early detection and efficient therapy remains a significant clinical challenge for this disease. Therefore, there is a need to identify novel tumor associated molecules to target for biomarker development and immunotherapy. In this regard, cancer testis antigens have emerged as a potential targets for developing novel clinical biomarkers and immunotherapy for various malignancies. These germ cell specific proteins exhibit aberrant expression in cancer cells and contribute in tumorigenesis. Owing to their unique expression profile and immunogenicity in cancer patients, cancer testis antigens are clinically referred as the most promising tumor associated antigens. Several cancer testis antigens have been studied in colorectal cancer but none of them could be used in clinical practice. This review is an attempt to address the promising cancer testis antigens in colorectal cancer and their possible clinical implications as biomarkers and immunotherapeutic targets with particular focus on challenges and future interventions.
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Phosphorylated alpha-enolase induces autoantibodies in HLA-DR8 pancreatic cancer patients and triggers HLA-DR8 restricted T-cell activation. Immunol Lett 2015; 167:11-6. [PMID: 26096821 DOI: 10.1016/j.imlet.2015.06.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/09/2015] [Accepted: 06/09/2015] [Indexed: 12/21/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-induced death in the Western World. In PDAC patients, alpha-enolase (ENOA), a glycolytic enzyme that also acts as plasminogen receptor, is up-regulated and elicits the production of autoantibodies. Our previous studies revealed that most PDAC patients specifically produce antibodies to Serine(419)phosphorylated ENOA (Ser(419)P-ENOA) isoforms (ENOA1,2), and that this humoral response correlates with a better clinical outcome. Since autoantibody production can be influenced by HLA polymorphisms, and the ENOA sequence presents multiple peptides predicted to preferentially bind HLA-DR molecules, including the peptide containing Ser(419), we hypothesized that the presence of autoantibodies against ENOA1,2 is associated with specific HLA-DRB1 alleles. Here, we demonstrate that the HLA-DRB1*08 allele is significantly more frequent in PDAC patients with autoantibodies to ENOA1,2 (ENOA1,2(+), 8%) compared to healthy controls (3%, p=0.0112). We observed that a Ser(419)P-ENOA peptide, bioinformatically predicted to bind with high affinity to the HLA-DR8 allele coded by HLA-DRB1*08:01 or *08:04 alleles, was able to activate specific CD4(+) T cell clones derived from a HLA-DRB1*08:01. Thus complexes of the Ser(419)P-ENOA peptide with the HLA that trigger T-cell signaling might be relevant for induction of anti-tumor immune response.
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13
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OVA12, a novel tumor antigen, promotes cancer cell growth and inhibits 5-fluorouracil-induced apoptosis. Cancer Lett 2015; 357:141-151. [DOI: 10.1016/j.canlet.2014.11.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 11/11/2014] [Accepted: 11/11/2014] [Indexed: 11/22/2022]
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Domae S, Ono T, Sasaki A. Cancer/testis antigens: A prospective reagent as diagnostic and immunotherapeutic targets for squamous cell carcinoma of the head and neck. JAPANESE DENTAL SCIENCE REVIEW 2014. [DOI: 10.1016/j.jdsr.2014.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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15
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Kim S, Hong JW, Cho WD, Moon YR, Yoon SS, Kim MY, Hong KP, Lee YM, Yi JH, Ham YJ, Rah HC, Kim SR, Song HG. Characterization of Two Novel mAbs Recognizing Different Epitopes on CD43. Immune Netw 2014; 14:164-70. [PMID: 24999313 PMCID: PMC4079823 DOI: 10.4110/in.2014.14.3.164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 05/26/2014] [Accepted: 06/01/2014] [Indexed: 12/01/2022] Open
Abstract
JL1, a specific epitope on CD43, is a potential biomarker for the diagnosis of acute leukemia. Although qualitative assays for detecting leukemia-specific CD43 exist, there is a need to develop quantitative assays for the same. Here, we developed two novel monoclonal antibodies (mAbs), 2C8 and 8E10, recognizing different epitopes on CD43. These clones are capable of pairing with YG5, another mAb against JL1 epitope, because they were selectively obtained using sandwich ELISA. Antigens recognized by 2C8 and 8E10 were confirmed as CD43 by western blotting using the CD43-hFC recombinant protein. When expression on various leukemic cell lines was investigated, 2C8 and 8E10 displayed a disparity in the distribution of the epitope. Enzyme assays revealed that these mAbs recognized a sialic acid-dependent epitope on CD43. Using normal thymus and lymph node paraffin-embedded tissues, we confirmed a difference in the epitopes recognized by the two mAbs that was predicted based on the maturity of the cells in the tissue. In summary, we developed and characterized two mAbs, 2C8 and 8E10, which can be used with YG5 in a sandwich ELISA for detecting leukemia-specific CD43.
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Affiliation(s)
- Soseul Kim
- Department of Pathology, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea. ; Research Institute, DiNonA Inc, Iksan 570-912, Korea
| | | | - Woon-Dong Cho
- Department of Pathology, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea
| | - Yoo Ri Moon
- Department of Pathology, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea. ; Research Institute, DiNonA Inc, Iksan 570-912, Korea
| | | | - Min-Young Kim
- Department of Pathology, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea
| | - Kwon Pyo Hong
- Research Institute, DiNonA Inc, Iksan 570-912, Korea
| | - Yong-Moon Lee
- Department of Pathology, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea
| | | | - Young Jun Ham
- Research Institute, DiNonA Inc, Iksan 570-912, Korea. ; Graduate School of Health Science Convergence, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea
| | - Hyung Chul Rah
- Graduate School of Health Science Convergence, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea
| | - Seung Ryul Kim
- Graduate School of Health Science Convergence, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea
| | - Hyung Geun Song
- Department of Pathology, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea. ; Graduate School of Health Science Convergence, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea
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Rao W, Li H, Song F, Zhang R, Yin Q, Wang Y, Xi Y, Ge H. OVA66 increases cell growth, invasion and survival via regulation of IGF-1R–MAPK signaling in human cancer cells. Carcinogenesis 2014; 35:1573-81. [DOI: 10.1093/carcin/bgu070] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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17
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OVA66, a tumor associated protein, induces oncogenic transformation of NIH3T3 cells. PLoS One 2014; 9:e85705. [PMID: 24633332 PMCID: PMC3954546 DOI: 10.1371/journal.pone.0085705] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 11/29/2013] [Indexed: 11/19/2022] Open
Abstract
The tumor associated antigen OVA66 has been demonstrated to be highly expressed in malignant tumors and implicated in various cellular processes. To further elucidate its oncogenic character, we established an OVA66 stably overexpressed NIH3T3 cell line and a vector transfected control, named NIH3T3-flagOVA66 and NIH3T3-mock, respectively. NIH3T3-flagOVA66 cells showed faster cell cycling, proliferation, cell migration and more resistance to 5-fluorouracil-induced apoptosis. When NIH3T3-flagOVA66 and NIH3T3-mock cells were injected into nude mice for xenograft tumorigenicity assays, the NIH3T3-flagOVA66 cells formed tumors whereas no tumors were observed in mice inoculated with NIH3T3-mock cells. Analysis of PI3K/AKT and ERK1/2 MAPK signaling pathways by serum stimulation indicated hyperactivation of AKT and ERK1/2 in NIH3T3-flagOVA66 cells compared with NIH3T3-mock cells, while a decreased level of p-AKT and p-ERK1/2 were observed in OVA66 knocked down HeLa cells. To further validate if the p-AKT or p-ERK1/2 is essential for OVA66 induced oncogenic transformation, we treated the cells with the PI3K/AKT specific inhibitor LY294002 and the ERK1/2 MAPK specific inhibitor PD98059 and found either inhibitor can attenuate the cell colony forming ability in soft agar and the cell viability of NIH3T3-flagOVA66 cells, suggesting aberrantly activated AKT and ERK1/2 signaling be indispensible of the tumorigenic role of OVA66. Our results indicate that OVA66 is important in oncogenic transformation, promoting proliferation, cell migration and reducing apoptosis via hyperactivating PI3K/AKT and ERK1/2 MAPK signaling pathway. Thus, OVA66 might be a novel target for early detection, prevention and treatment of tumors in the future.
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Järås K, Anderson K. Autoantibodies in cancer: prognostic biomarkers and immune activation. Expert Rev Proteomics 2014; 8:577-89. [DOI: 10.1586/epr.11.48] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Abstract
A large volume of data relevant to immunology research has accumulated due to sequencing of genomes of the human and other model organisms. At the same time, huge amounts of clinical and epidemiologic data are being deposited in various scientific literature and clinical records. This accumulation of the information is like a goldmine for researchers looking for mechanisms of immune function and disease pathogenesis. Thus the need to handle this rapidly growing immunological resource has given rise to the field known as immunoinformatics. Immunoinformatics, otherwise known as computational immunology, is the interface between computer science and experimental immunology. It represents the use of computational methods and resources for the understanding of immunological information. It not only helps in dealing with huge amount of data but also plays a great role in defining new hypotheses related to immune responses. This chapter reviews classical immunology, different databases, and prediction tool. Further, it briefly describes applications of immunoinformatics in reverse vaccinology, immune system modeling, and cancer diagnosis and therapy. It also explores the idea of integrating immunoinformatics with systems biology for the development of personalized medicine. All these efforts save time and cost to a great extent.
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Affiliation(s)
- Namrata Tomar
- Machine Intelligence Unit, Indian Statistical Institute, 203 B.T. Road, Kolkata, 700108, India,
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20
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Chen LC, Zhang HY, Qin ZY, Wang Y, Mao Y, Yao Y, Zhou LF. Serological identification of URGCP as a potential biomarker for glioma. CNS Neurosci Ther 2013; 20:301-7. [PMID: 24308561 DOI: 10.1111/cns.12214] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 11/07/2013] [Accepted: 11/08/2013] [Indexed: 12/31/2022] Open
Abstract
AIM Glioblastoma multiforme (GBM) is one of the most frequent human brain tumor and causes dismal outcome. To identify tumor-associated antigens in GBM patients may find potential diagnostic markers and immunotherapeutic targets. In this study, we identified a gene termed URGCP using the serological identification of antigens by recombinant A2B5 positive glioma cDNA library. The gene product of URGCP is immunogenic in GBM after tested in allogenic patients serum screening. METHODS AND RESULTS GBM patients with an auto-antibody response against URGCP show longer survival than those without URGCP response. In additional, we show that URGCP was high expression in most GBM tissues and cell lines compared with normal brain tissues and majorly co-expressed with stem cell marker A2B5. CONCLUSION We identified a potential new biomarker of GBM, URGCP. The findings indicate that URGCP is immunogenic in human GBM and suggest its potential use as diagnostic and immunotherapeutic for GBM patients.
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Affiliation(s)
- Ling-Chao Chen
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
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21
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Iheagwara UK, Beatty PL, Van PT, Ross TM, Minden JS, Finn OJ. Influenza virus infection elicits protective antibodies and T cells specific for host cell antigens also expressed as tumor-associated antigens: a new view of cancer immunosurveillance. Cancer Immunol Res 2013; 2:263-73. [PMID: 24778322 DOI: 10.1158/2326-6066.cir-13-0125] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Most tumor-associated antigens (TAA) are self-molecules that are abnormally expressed in cancer cells and become targets of antitumor immune responses. Antibodies and T cells specific for some TAAs have been found in healthy individuals and are associated with lowered lifetime risk for developing cancer. Lower risk for cancer has also been associated with a history of febrile viral diseases. We hypothesized that virus infections could lead to transient expression of abnormal forms of self-molecules, some of which are TAAs; facilitated by the adjuvant effects of infection and inflammation, these molecules could elicit specific antibodies, T cells, and lasting immune memory simultaneously with immunity against viral antigens. Such infection-induced immune memory for TAA would be expected to provide life-long immune surveillance of cancer. Using influenza virus infection in mice as a model system, we tested this hypothesis and demonstrated that influenza-experienced mice control 3LL mouse lung tumor challenge better than infection-naive control mice. Using 2D-difference gel electrophoresis and mass spectrometry, we identified numerous molecules, some of which are known TAAs, on the 3LL tumor cells recognized by antibodies elicited by two successive influenza infections. We studied in detail immune responses against glyceraldehyde-3-phosphate dehydrogenase (GAPDH), histone H4, HSP90, malate dehydrogenase 2, and annexin A2, all of which were overexpressed in influenza-infected lungs and in tumor cells. Finally, we show that immune responses generated through vaccination against peptides derived from these antigens correlated with improved tumor control.
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Affiliation(s)
- Uzoma K Iheagwara
- Authors' Affiliations: Departments of Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania
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Affiliation(s)
- Yutaka Kawakami
- Division of Cellular Signaling; Institute for Advanced Medical Research, Keio University School of Medicine; 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan
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Zaenker P, Ziman MR. Serologic autoantibodies as diagnostic cancer biomarkers--a review. Cancer Epidemiol Biomarkers Prev 2013; 22:2161-81. [PMID: 24057574 DOI: 10.1158/1055-9965.epi-13-0621] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Current diagnostic techniques used for the early detection of cancers are successful but subject to detection bias. A recent focus lies in the development of more accurate diagnostic tools. An increase in serologic autoantibody levels has been shown to precede the development of cancer disease symptoms. Therefore, autoantibody levels in patient blood serum have been proposed as diagnostic biomarkers for early-stage diagnosis of cancers. Their clinical application has, however, been hindered by low sensitivity, specificity, and low predictive value scores. These scores have been shown to improve when panels of multiple diagnostic autoantibody biomarkers are used. A five-marker biomarker panel has been shown to increase the sensitivity of prostate cancer diagnosis to 95% as compared with 12.2% for prostate-specific antigen alone. New potential biomarker panels were also discovered for lung, colon, and stomach cancer diagnosis with sensitivity of 76%, 65.4%, and 50.8%, respectively. Studies in breast and liver cancer, however, seem to favor single markers, namely α-2-HS-glycoprotein and des-γ-carboxyprothrombin with sensitivities of 79% and 89% for the early detection of the cancers. The aim of this review is to discuss the relevance of autoantibodies in cancer diagnosis and to outline the current methodologies used in the detection of autoantibodies. The review concludes with a discussion of the autoantibodies currently used in the diagnosis of cancers of the prostate, breast, lung, colon, stomach, and liver. A discussion of the potential future use of autoantibodies as diagnostic cancer biomarkers is also included in this review.
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Affiliation(s)
- Pauline Zaenker
- Authors' Affiliations: School of Medical Sciences, Edith Cowan University, Perth; and Department of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia
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Abstract
Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types, but owing to the heterogeneity of cancer theories of common reaction mechanisms seem to be obsolete. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor β (TGFβ), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4). Clinical data were analysed in a non-quantitative descriptive manner and interpreted with regard to experimentally established physiological cytokine interactions. The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFβ. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12-interferon-γ-HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient's prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer.
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Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013; 95:19-47. [PMID: 23238534 DOI: 10.1097/tp.0b013e31827a19cc] [Citation(s) in RCA: 602] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.
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Abstract
The varied landscape of the adaptive immune response is determined by the peptides presented by immune cells, derived from viral or microbial pathogens or cancerous cells. The study of immune biomarkers or antigens is not new and classical methods such as agglutination, enzyme-linked immunosorbent assay, or Western blotting have been used for many years to study the immune response to vaccination or disease. However, in many of these traditional techniques, protein or peptide identification has often been the bottleneck. Recent advances in genomics and proteomics, has led to many of the rapid advances in proteomics approaches. Immunoproteomics describes a rapidly growing collection of approaches that have the common goal of identifying and measuring antigenic peptides or proteins. This includes gel based, array based, mass spectrometry, DNA based, or in silico approaches. Immunoproteomics is yielding an understanding of disease and disease progression, vaccine candidates, and biomarkers. This review gives an overview of immunoproteomics and closely related technologies that are used to define the full set of antigens targeted by the immune system during disease.
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Affiliation(s)
- Kelly M Fulton
- Human Health Therapeutics, National Research Council Canada, Ottawa, ON, Canada
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27
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Zheng J, Liu P, Yang X. YB-1 immunization combined with regulatory T-cell depletion induces specific T-cell responses that protect against neuroblastoma in the early stage. Acta Biochim Biophys Sin (Shanghai) 2012; 44:1006-14. [PMID: 23169344 DOI: 10.1093/abbs/gms089] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy. Currently, no effective clinical treatments are available for advanced neuroblastoma. In a previous study, we screened Y Box protein 1 (YB-1) as a potential neuroblastoma-associated antigen from sera of AGN2a-immunized mice by serological analysis of recombinant cDNA expression libraries technique. The aim of this study is to explore if YB-1 immunization in the context of Treg depletion could induce protective immune response against the neuroblastoma in mice. YB-1 was expressed and purified by pET-15b prokaryotic expression system. It was demonstrated that anti-YB-1 CD8(+) T-cell responses could be induced by AGN2a immunization, and the strongest CD8(+) T-cell responses against AGN2a were induced by YB-1-immunized mice in the context of Treg depletion compared with YB-1 only immunization group and control group. Importantly, the survival rate of mice treated with YB-1 immunization combined with Treg depletion was 80% when challenged by 1 × 10(4) AGN2a cells, significantly higher than that of mice immunized with YB-1 alone (P < 0.01). Furthermore, T-cell adoptive therapy showed that the neuroblastoma growth was inhibited when T cells or splenic cells from YB-1-immunized mice with Treg depletion were transferred to AGN2a bearing mice. Both CD4(+) and CD8(+) T cells were involved in the anti-neuroblastoma responses induced by YB-1 immunization combined with Treg depletion. These results indicated that YB-1 immunization combined with Treg depletion could induce specific T-cell responses against neuroblastoma and could be a potential strategy for the prevention and treatment of neuroblastoma in the early stage.
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Affiliation(s)
- Jin Zheng
- The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China
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28
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Buus S, Rockberg J, Forsström B, Nilsson P, Uhlen M, Schafer-Nielsen C. High-resolution mapping of linear antibody epitopes using ultrahigh-density peptide microarrays. Mol Cell Proteomics 2012; 11:1790-800. [PMID: 22984286 PMCID: PMC3518105 DOI: 10.1074/mcp.m112.020800] [Citation(s) in RCA: 153] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Antibodies empower numerous important scientific, clinical, diagnostic, and industrial applications. Ideally, the epitope(s) targeted by an antibody should be identified and characterized, thereby establishing antibody reactivity, highlighting possible cross-reactivities, and perhaps even warning against unwanted (e.g. autoimmune) reactivities. Antibodies target proteins as either conformational or linear epitopes. The latter are typically probed with peptides, but the cost of peptide screening programs tends to prohibit comprehensive specificity analysis. To perform high-throughput, high-resolution mapping of linear antibody epitopes, we have used ultrahigh-density peptide microarrays generating several hundred thousand different peptides per array. Using exhaustive length and substitution analysis, we have successfully examined the specificity of a panel of polyclonal antibodies raised against linear epitopes of the human proteome and obtained very detailed descriptions of the involved specificities. The epitopes identified ranged from 4 to 12 amino acids in size. In general, the antibodies were of exquisite specificity, frequently disallowing even single conservative substitutions. In several cases, multiple distinct epitopes could be identified for the same target protein, suggesting an efficient approach to the generation of paired antibodies. Two alternative epitope mapping approaches identified similar, although not necessarily identical, epitopes. These results show that ultrahigh-density peptide microarrays can be used for linear epitope mapping. With an upper theoretical limit of 2,000,000 individual peptides per array, these peptide microarrays may even be used for a systematic validation of antibodies at the proteomic level.
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Affiliation(s)
- Søren Buus
- Laboratory of Experimental Immunology, University of Copenhagen, Copenhagen N, Denmark.
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29
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Abstract
Because several antigenic peptides of human tumors that are recognized by T-lymphocytes have been identified, immune responses against cancer can now be artificially manipulated. Furthermore, since T-lymphocytes have been found to play an important role in the rejection of tumors by the host and also to have antigen-specific proliferative potentials and memory mechanisms, T-lymphocytes are thought to play a central role in cancer vaccination. Although multidisciplinary therapies have been attempted for the treatment of gliomas, the results remain unsatisfactory. For the development of new therapies against gliomas, it is required to identify tumor antigens as targets for specific immunotherapy. In this chapter, recent progress in research on glioma antigens is described.
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Affiliation(s)
- Masahiro Toda
- Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan.
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30
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Creeden J, Junker F, Vogel-Ziebolz S, Rex D. Serum Tests for Colorectal Cancer Screening. Mol Diagn Ther 2012; 15:129-41. [DOI: 10.1007/bf03256403] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Desmetz C, Mange A, Maudelonde T, Solassol J. Autoantibody signatures: progress and perspectives for early cancer detection. J Cell Mol Med 2012; 15:2013-24. [PMID: 21651719 PMCID: PMC4394213 DOI: 10.1111/j.1582-4934.2011.01355.x] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Becoming invasive is a crucial step in cancer development, and the early spread of tumour cells is usually undetected by current imaging technologies. In patients with cancer and no signs of overt metastases, sensitive methods have been developed to identify circulating autoantibodies and their antigen counterparts in several cancers. These technologies are often based on proteomic approaches, and recent advances in protein and antibody microarrays have greatly facilitated the discovery of new antibody biomarkers in sera from cancer patients. Interestingly, in a clinical application setting, combinations of multiple autoantibody reactivities into panel assays have recently been proposed as relevant screening tests and validated in several independent trials. In addition, autoantibody signatures seem to be particularly relevant for early detection of cancer in high-risk cancer patients. In this review, we highlight the concept that immunogenic epitopes associated with the humoural response and key pathogenic pathways elicit serum autoantibodies that can be considered as relevant cancer biomarkers. We outline the proteomic strategies employed to identify and validate their use in clinical practice for cancer screening and diagnosis. We particularly emphasize the clinical utility of autoantibody signatures in several cancers. Finally, we discuss the challenges remaining for clinical validation.
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Affiliation(s)
- C Desmetz
- CHU Montpellier, Laboratoire de biologie cellulaire et hormonale, Hôpital Arnaud de Villeneuve, Montpellier, France
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Biragyn A, Longo DL. Neoplastic "Black Ops": cancer's subversive tactics in overcoming host defenses. Semin Cancer Biol 2012; 22:50-9. [PMID: 22257681 DOI: 10.1016/j.semcancer.2012.01.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 01/04/2012] [Indexed: 01/07/2023]
Abstract
Metastatic cancer is usually an incurable disease. Cancers have a broad repertoire of subversive tactics to defeat the immune system. They mimic self, they down-regulate MHC molecules so that T cells are blind to their presence, they interfere with antigen presentation, and they produce factors that can kill T cells or paralyze their response to antigens. Furthermore, the same powerful machinery designed to prevent harmful autoimmune responses is also acting to protect cancers. In particular, cancer is protected with the help of so-called regulatory immune cells. These unique subsets of cells, represented by almost every immune cell type, function to control responses of effector immune cells. In this review, we will discuss the evidence that cancer actively promotes cross-talk of regulatory immune cells to evade immunosurveillance. We will also discuss the role of a newly described cell type, regulatory B cells, by emphasizing their importance in suppression of antitumor immune responses. Thus, cancer not only directly suppresses immune function, but also recruits components of the immune system to become traitors and protect the tumor from immune attack.
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Affiliation(s)
- Arya Biragyn
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD 21224, United States.
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Bie L, Zhao G, Ju Y, Zhang B. Integrative genomic analysis identifies CCNB1 and CDC2 as candidate genes associated with meningioma recurrence. Cancer Genet 2011; 204:536-40. [DOI: 10.1016/j.cancergen.2011.08.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 07/28/2011] [Accepted: 08/11/2011] [Indexed: 11/15/2022]
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Bilusic M, Heery C, Madan RA. Immunotherapy in prostate cancer: emerging strategies against a formidable foe. Vaccine 2011; 29:6485-97. [PMID: 21741424 PMCID: PMC3605720 DOI: 10.1016/j.vaccine.2011.06.088] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 06/22/2011] [Accepted: 06/23/2011] [Indexed: 11/29/2022]
Abstract
Recent clinical trials have shown therapeutic vaccines to be promising treatment modalities against prostate cancer. Unlike preventive vaccines that teach the immune system to fight off specific microorganisms, therapeutic vaccines stimulate the immune system to recognize and attack certain cancer-associated proteins. Additional strategies are being investigated that combine vaccines and standard therapeutics, including radiation, chemotherapy, targeted therapies, and hormonal therapy, to optimize the vaccines' effects. Recent vaccine late-phase clinical trials have reported evidence of clinical benefit while maintaining excellent quality of life. One such vaccine, sipuleucel-T, was recently FDA-approved for the treatment of metastatic prostate cancer. Another vaccine, PSA-TRICOM, is also showing promise in completed and ongoing randomized multicenter clinical trials in both early- and late-stage prostate cancer. Clinical results available to date indicate that immune-based therapies could play a significant role in the treatment of prostate and other malignancies.
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Affiliation(s)
- Marijo Bilusic
- Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Christopher Heery
- Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Ravi A. Madan
- Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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Abstract
Hematologic malignancies were the first diseases in clinical oncology for which the potential of harnessing the immune system as targeted therapy was unequivocally demonstrated. Unfortunately, the use of this highly efficacious modality has been limited to only a subset of patients and diseases because of immune-mediated toxicities resulting from incomplete specificity, and disease-specific determinants of sensitivity versus resistance to immune effector mechanisms. Recent studies, however, have begun to elucidate the molecular basis of the observed clinical effects allowing the rational development of next generation of immunotherapeutic combinations. We discuss here cancer antigen targets in hematologic malignancies and the specific approaches to induce immunity being pursued, the importance of modulating the host immunoregulatory environment, and the special features of immunological monitoring in clinical investigation. The hematologic malignancies represent an ideal setting for the development of immunotherapy due to logistical, clinical monitoring, and disease biology factors and may represent an exemplar for immune-based treatment in other cancer types.
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Affiliation(s)
- Christopher S Hourigan
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231-1000, USA
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Abstract
The human antibody response has special significance in the ongoing efforts to develop a protective HIV vaccine. The observation that a subset of HIV infected individuals, who do not develop AIDS, have a broadly neutralizing antibody response has drawn attention to deciphering the nature of this response. It is hoped that an understanding of these protective antibodies, developed over time in response to the ongoing accumulation of mutations in the infecting virus, will facilitate the development of a vaccine that can elicit a similar response. This strategy will be greatly aided by the identification of broadly neutralizing monoclonal HIV antibodies from infected individuals. Several methods have been utilized to isolate and characterize individual antibodies from the human repertoire and each of these methods has been applied to the generation of broadly neutralizing HIV antibodies, albeit with differing rates of success. This review describes several of these methods including human hybridoma; EBV transformation; non-immortalized B cell culture; clonal sorting; and combinatorial display. Key considerations used in the comparison of different methods includes: efficiency of interrogation of an individual's entire repertoire; assay formats that can be used to screen for antibodies of interest (i.e., binding versus biological assays); and the ability to recover native antibody heavy and light chain pairs.
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Desmetz C, Lacombe J, Mange A, Maudelonde T, Solassol J. Autoanticorps et diagnostic précoce des cancers. Med Sci (Paris) 2011; 27:633-8. [DOI: 10.1051/medsci/2011276016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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State of the art in tumor antigen and biomarker discovery. Cancers (Basel) 2011; 3:2554-96. [PMID: 24212823 PMCID: PMC3757432 DOI: 10.3390/cancers3022554] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Revised: 05/24/2011] [Accepted: 05/27/2011] [Indexed: 12/22/2022] Open
Abstract
Our knowledge of tumor immunology has resulted in multiple approaches for the treatment of cancer. However, a gap between research of new tumors markers and development of immunotherapy has been established and very few markers exist that can be used for treatment. The challenge is now to discover new targets for active and passive immunotherapy. This review aims at describing recent advances in biomarkers and tumor antigen discovery in terms of antigen nature and localization, and is highlighting the most recent approaches used for their discovery including “omics” technology.
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Chiriva-Internati M. Sperm Protein 17: Clinical Relevance of a Cancer/Testis Antigen, from Contraception to Cancer Immunotherapy, and Beyond. Int Rev Immunol 2011; 30:138-49. [DOI: 10.3109/08830185.2011.569903] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Xie C, Kim HJ, Haw JG, Kalbasi A, Gardner BK, Li G, Rao J, Chia D, Liong M, Punzalan RR, Marks LS, Pantuck AJ, de la Taille A, Wang G, Mukouyama H, Zeng G. A novel multiplex assay combining autoantibodies plus PSA has potential implications for classification of prostate cancer from non-malignant cases. J Transl Med 2011; 9:43. [PMID: 21504557 PMCID: PMC3102624 DOI: 10.1186/1479-5876-9-43] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Accepted: 04/19/2011] [Indexed: 12/18/2022] Open
Abstract
Background The lack of sufficient specificity and sensitivity among conventional cancer biomarkers, such as prostate specific antigen (PSA) for prostate cancer has been widely recognized after several decades of clinical implications. Autoantibodies (autoAb) among others are being extensively investigated as potential substitute markers, but remain elusive. One major obstacle is the lack of a sensitive and multiplex approach for quantifying autoAb against a large panel of clinically relevant tumor-associated antigens (TAA). Methods To circumvent preparation of phage lysates and purification of recombinant proteins, we identified B cell epitopes from a number of previously defined prostate cancer-associated antigens (PCAA). Peptide epitopes from cancer/testis antigen NY-ESO-1, XAGE-1b, SSX-2,4, as well as prostate cancer overexpressed antigen AMACR, p90 autoantigen, and LEDGF were then conjugated with seroMAP microspheres to allow multiplex measurement of autoAb present in serum samples. Moreover, simultaneous quantification of autoAb plus total PSA was achieved in one reaction, and termed the "A+PSA" assay. Results Peptide epitopes from the above 6 PCAA were identified and confirmed that autoAb against these peptide epitopes reacted specifically with the full-length protein. A pilot study was conducted with the A+PSA assay using pre-surgery sera from 131 biopsy-confirmed prostate cancer patients and 121 benign prostatic hyperplasia and/or prostatitis patients. A logistic regression-based A+PSA index was found to enhance sensitivities and specificities over PSA alone in distinguishing prostate cancer from nonmalignant cases. The A+PSA index also reduced false positive rate and improved the area under a receiver operating characteristic curve. Conclusions The A+PSA assay represents a novel platform that integrates autoAb signatures with a conventional cancer biomarker, which may aid in the diagnosis and prognosis of prostate cancer and others.
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Affiliation(s)
- Chong Xie
- Department of Urology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1738, USA
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Capello M, Ferri-Borgogno S, Cappello P, Novelli F. α-Enolase: a promising therapeutic and diagnostic tumor target. FEBS J 2011; 278:1064-74. [PMID: 21261815 DOI: 10.1111/j.1742-4658.2011.08025.x] [Citation(s) in RCA: 205] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
α-enolase (ENOA) is a metabolic enzyme involved in the synthesis of pyruvate. It also acts as a plasminogen receptor and thus mediates activation of plasmin and extracellular matrix degradation. In tumor cells, ΕΝΟΑ is upregulated and supports anaerobic proliferation (Warburg effect), it is expressed at the cell surface, where it promotes cancer invasion, and is subjected to a specific array of post-translational modifications, namely acetylation, methylation and phosphorylation. Both ENOA overexpression and its post-translational modifications could be of diagnostic and prognostic value in cancer. This review will discuss recent information on the biochemical, proteomics and immunological characterization of ENOA, particularly its ability to trigger a specific humoral and cellular immune response. In our opinion, this information can pave the way for effective new therapeutic and diagnostic strategies to counteract the growth of the most aggressive human disease.
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Affiliation(s)
- Michela Capello
- Department of Medicine and Experimental Oncology, Center for Experimental Research and Medical Studies (CeRMS), San Giovanni Battista Hospital, University of Turin, Turin, Italy
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Fratta E, Coral S, Covre A, Parisi G, Colizzi F, Danielli R, Nicolay HJM, Sigalotti L, Maio M. The biology of cancer testis antigens: putative function, regulation and therapeutic potential. Mol Oncol 2011; 5:164-82. [PMID: 21376678 DOI: 10.1016/j.molonc.2011.02.001] [Citation(s) in RCA: 273] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Revised: 01/31/2011] [Accepted: 02/03/2011] [Indexed: 12/14/2022] Open
Abstract
Cancer testis antigens (CTA) are a large family of tumor-associated antigens expressed in human tumors of different histological origin, but not in normal tissues except for testis and placenta. This tumor-restricted pattern of expression, together with their strong in vivo immunogenicity, identified CTA as ideal targets for tumor-specific immunotherapeutic approaches, and prompted the development of several clinical trials of CTA-based vaccine therapy. Driven by this practical clinical interest, a more detailed characterization of CTA biology has been recently undertaken. So far, at least 70 families of CTA, globally accounting for about 140 members, have been identified. Most of these CTA are expressed during spermatogenesis, but their function is still largely unknown. Epigenetic events, particularly DNA methylation, appear to be the primary mechanism regulating CTA expression in both normal and transformed cells, as well as in cancer stem cells. In view of the growing interest in CTA biology, the aim of this review is to provide the most recent information on their expression, regulation and function, together with a brief summary of the major clinical trials involving CTA as therapeutic agents. The pharmacologic modulation of CTA expression profiles on neoplastic cells by DNA hypomethylating drugs will also be discussed as a feasible approach to design new combination therapies potentially able to improve the clinical efficacy of currently adopted CTA-based immunotherapeutic regimens in cancer patients.
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Affiliation(s)
- Elisabetta Fratta
- Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Via Franco Gallini 2, 33081 Aviano, Italy
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Kohler ME, Johnson BD, Palen K, Chen QR, Khan J, Orentas RJ. Tumor antigen analysis in neuroblastoma by serological interrogation of bioinformatic data. Cancer Sci 2010; 101:2316-24. [PMID: 20718755 DOI: 10.1111/j.1349-7006.2010.01694.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: 11/29/2022] Open
Abstract
The identification of tumor antigens remains a major objective in tumor immunology, especially in pediatric malignancies where solid tumors often do not express a single dominant antigen. Methods such as the Serological Screening of Recombinant cDNA Expression Libraries (SEREX) have been used in the discovery of tumor-expressed proteins by virtue of their ability to induce an antibody response. To focus and accelerate this approach, we first identified candidate antigens by gene expression profiling data from clinical neuroblastoma specimens and then used an animal model to generate an antibody response to an engineered cell-based vaccine. Candidate tumor antigens were expressed as recombinant proteins in a mammalian system and screened for antibody recognition using serum from mice vaccinated with a neuroblastoma cell-based vaccine engineered to express CD80 and CD86, with or without Treg depletion. Through this procedure, the never in mitosis A (NIMA)-related kinase NEK2 was identified as a tumor-associated antigen. Direct testing of serum from patients newly diagnosed with neuroblastoma showed specific serological responses in two of 20 patients. Although NEK2 was not universally recognized, it may serve as a tumor antigen for some patients.
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Affiliation(s)
- M Eric Kohler
- Department of Pediatrics Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin , USA
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Abstract
IMPORTANCE OF THE FIELD The number of disease-associated protein targets has significantly increased over the past decade due to advances in molecular and cellular biology technologies, human genetic mapping efforts and information gathered from the human genome project. The identification of gene products that appear to be involved in supporting the underlying cause of disease has offered the biopharmaceutical industry an opportunity to develop compounds that can specifically target these molecules to improve therapeutic responses and lower the risk of unwanted side effects that are commonly seen in traditional small chemical-based medicines. AREAS COVERED IN THIS REVIEW An overview of targeted drug therapies is presented in this review. We include a review of the various classes of targeted therapeutic agents, the types of disease-associated molecules being targeted by these agents and the challenges currently being encountered for the successful development of these various platforms for the treatment of disease. WHAT THE READER WILL GAIN An understanding of the current targeted therapy landscape, the discovery and selection of disease-specific gene products that are being targeted, and an overview of targeted therapies in preclinical and clinical studies. A description of the various targeted therapeutic platforms, target selection criteria and examples of each are discussed in order to provide the reader with the current status of the field and emerging areas of targeted therapy discovery and development. TAKE HOME MESSAGE Novel medications are in demand for the treatment of serious medical conditions including cancer, autoimmune, infectious and metabolic diseases. Targeted therapies offer a way to develop very specific treatments for serious medical conditions while concomitantly resulting in little to no off-target toxicity. Targeted therapies provide an opportunity to develop personalized medicines with superior treatment modalities for the patient and a better quality of life.
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Tomar N, De RK. Immunoinformatics: an integrated scenario. Immunology 2010; 131:153-68. [PMID: 20722763 PMCID: PMC2967261 DOI: 10.1111/j.1365-2567.2010.03330.x] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Revised: 06/12/2010] [Accepted: 06/21/2010] [Indexed: 12/11/2022] Open
Abstract
Genome sequencing of humans and other organisms has led to the accumulation of huge amounts of data, which include immunologically relevant data. A large volume of clinical data has been deposited in several immunological databases and as a result immunoinformatics has emerged as an important field which acts as an intersection between experimental immunology and computational approaches. It not only helps in dealing with the huge amount of data but also plays a role in defining new hypotheses related to immune responses. This article reviews classical immunology, different databases and prediction tools. It also describes applications of immunoinformatics in designing in silico vaccination and immune system modelling. All these efforts save time and reduce cost.
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Affiliation(s)
- Namrata Tomar
- Machine Intelligence Unit, Indian Statistical Institute, Kolkata, India
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Whiteside TL. Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression. Expert Opin Biol Ther 2010; 10:1019-35. [PMID: 20415597 DOI: 10.1517/14712598.2010.482207] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
IMPORTANCE OF THE FIELD Immunotherapy of cancer has not improved disease-free or overall patient survival. The lack of concordance between immunological and clinical responses in cancer immunotherapy trials is thought to result from the pervasive presence of tumor-driven immune suppression that allows tumor to escape and that has not been adequately targeted by current therapies. AREAS COVERED IN THIS REVIEW Because multiple mechanisms of tumor induced suppression have been identified and shown to contribute to tumor escape, the opportunity arises to interfere with these mechanisms. A range of known tumor-derived inhibitors can now be blocked or neutralized by biologic or metabolic agents. Used alone or in combination with each other or with conventional cancer therapies, these agents offer novel therapeutic strategies for the control of tumor escape. WHAT THE READER WILL GAIN This review deals with currently available inhibitors for counteracting tumor immune escape. The restoration of effective anti-tumor immunity in patients with cancer will require new approaches aiming at: i) protection of immune cells from adverse effects of myeloid-derived suppressor cells, regulatory T cells or inhibitory factors thus enhancing effector functions; and ii) prolonging survival of central memory T cells, thus ensuring long-term protection. TAKE HOME MESSAGE Inhibitors of mechanisms responsible for tumor escape could restore anti-tumor immune responses in patients with cancer.
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Affiliation(s)
- Theresa L Whiteside
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pathology, 5117 Centre Avenue, Pittsburgh, 15213 USA.
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Yao Y, Wu Z, Zhou Q. [Autoantibodies as the early diagnostic biomarkers for lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2010; 13:903-7. [PMID: 20840821 PMCID: PMC6000346 DOI: 10.3779/j.issn.1009-3419.2010.09.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Revised: 06/07/2010] [Indexed: 12/05/2022]
Affiliation(s)
- Yibing Yao
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenviroment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
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Alahmad A, Preuss KD, Schenk J, Füreder W, Schrezenmeier H, Müller-Lantzsch N, Schubert J, Pfreundschuh M. Desmoplakin and KIF20B as target antigens in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2010; 151:273-80. [DOI: 10.1111/j.1365-2141.2010.08345.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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VanDuijn MM, Dekker LJM, Zeneyedpour L, Smitt PAES, Luider TM. Immune responses are characterized by specific shared immunoglobulin peptides that can be detected by proteomic techniques. J Biol Chem 2010; 285:29247-53. [PMID: 20615873 DOI: 10.1074/jbc.m110.139071] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
In the adaptive immune response, immunoglobulins develop that bind specifically to the antigens to which the organism was exposed. Immunoglobulins may bind to known or unknown antigens in a variety of diseases and have been used in the past to identify novel antigens for use as a biomarker. We propose that the immunoglobulins themselves could also be used as biomarkers in antibody-mediated disease. In this proteomic study, rats were immunized with one of two purified antigens, and immunoglobulins from pre- and postimmune sera were analyzed with nano-LC coupled mass spectrometry. It was found that the two treatment groups could be distinguished based on cluster analysis of the immunoglobulin peptides from the immune sera. In addition, we identified 684 specific peptides that were differentially present in one of the two treated groups. We could find an amino acid sequence for 44% of the features in the mass spectra by combining database-driven and de novo sequencing techniques. The latter were essential for sequence identification, as the more common database-driven approach suffers from a poor representation of immunoglobulins in the available databases. Our data show that the development of immunoglobulins during an immune response is not a fully random process, but that instead selection pressures exist that favor the best binding amino acid sequences, and that this selection is shared between different animals. This finding implies that immunoglobulin peptides could indeed be a powerful and easily accessible class of biomarkers.
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Staquicini FI, Moeller BJ, Arap W, Pasqualini R. Combinatorial vascular targeting in translational medicine. Proteomics Clin Appl 2010; 4:626-32. [DOI: 10.1002/prca.200900213] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Revised: 02/23/2010] [Accepted: 02/24/2010] [Indexed: 12/12/2022]
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