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Identification of tumor antigens and immune subtypes of hepatocellular carcinoma for mRNA vaccine development

World Journal of Gastrointestinal Oncology 2023年第10期15卷 1717-1738页

作者： Tai-Liang Lu Cheng-Long Li Yong-Qiang Gong Fu-Tao Hou Chao-Wu Chen Department of General Surgery Hunan Provincial People’s HospitalThe First Affiliated Hospital of Hunan Normal UniversityChangsha 410005Hunan ProvinceChina

BACKGROUND mRNA vaccines have been investigated in multiple tumors,but limited studies have been conducted on their use for hepatocellular carcinoma(HCC).AIM To identify candidate mRNA vaccine antigens for HCC and suitable subpopu-lations for mRNA vaccination.METHODS Gene expression profiles and clinical information of HCC datasets were obtained from International Cancer Genome Consortium and The Cancer Genome Atlas.Genes with somatic mutations and copy number variations were identified by cBioPortal analysis.The differentially expressed genes with significant prognostic value were identified by Gene Expression Profiling Interactive Analysis 2 website analysis.The Tumor Immune Estimation Resource database was used to assess the correlation between candidate antigens and the abundance of antigen-presenting cells(APCs).Tumor-associated antigens were overexpressed in tumors and associated with prognosis,genomic alterations,and APC infiltration.A consensus cluster analysis was performed with the Consensus Cluster Plus package to identify the immune subtypes.The weighted gene coexpression network analysis(WGCNA)was used to determine the candidate biomarker molecules for appropriate populations for mRNA vaccines.immune subtypes showed distinct cellular and clinical characteristics.The IS1 and IS3 immune subtypes were immunologically“cold”.The IS2 and IS4 immune subtypes were immunologically“hot”,and the immune checkpoint genes and immunogenic cell death genes were upregulated in these subtypes.IS1-related modules were identified with the WGCNA algorithm.Ultimately,five hub genes(RBP4,KNG1,METTL7A,F12,and ABAT)were identified,and they might be potential biomarkers for mRNA vaccines.CONCLUSION AURKA,CCNB1,CDC25C,CDK1,TRIP13,PES1,MCM3,PPM1G,NEK2,KIF2C,PTTG1,KPNA2,and PRC1 have been identified as candidate HCC antigens for mRNA vaccine development.The IS1 and IS3 immune subtypes are suitable populations for mRNA vaccination.RBP4,KNG1,METTL7A,F12,and ABAT are potential biomarkers for mRNA vaccines.

关键词： mRNA vaccine Hepatocellular carcinoma Immunotype antigens Immune subtypes

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Targeting cancer testis antigens for biomarkers and immunotherapy in colorectal cancer: Current status and challenges

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World Journal of Gastrointestinal Oncology 2015年第12期7卷 492-502页

作者： Anil Suri Nirmala Jagadish Shikha Saini Namita Gupta Cancer Microarray Genes and Proteins Laboratory National Institute of Immunology

Colorectal cancer ranks third among the estimatedcancer 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 asso-ciated 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.

关键词： Cancer testis antigens Colorectal cancer Testis sp

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Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens

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World Journal of Gastroenterology 2018年第48期24卷 5418-5432页

作者： Sandra Wagner Christina S Mullins Michael Linnebacher Section of Molecular Oncology and Immunotherapy General SurgeryUniversity Medical Center

Therapeutic options for the treatment of colorectal cancer(CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hypermutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. Substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens(TAAs) and tumorspecific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptidebased vaccines achievable by adjuvants and immunestimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens-in CRC almost exclusively neoantigens-which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immunestimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.

关键词： Cancer vaccines Colorectal neoplasm Immunotherapy Neoplasm antigen tumor-associated antigens tumor-specific antigens Neoantigen(s)

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Reaction of antibodies to Campylobacter jejuni and cytolethal distending toxin B with tissues and food antigens

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World Journal of Gastroenterology 2019年第9期25卷 1050-1066页

作者： Aristo Vojdani Elroy Vojdani Immunosciences Lab. Inc. Los Angeles Cyrex Labs LLC. Phoenix Department of Preventive Medicine Loma Linda University School of Medicine Regenera Medical Los Angeles

BACKGROUND The bacteria Campylobacter jejuni(C. jejuni) is commonly associated with GuillaneBarré syndrome(GBS) and irritable bowel syndrome(IBS), but studies have also linked it with Miller Fisher syndrome, reactive arthritis and other disorders, some of which are autoimmune. It is possible that C. jejuni and its toxins may be crossreactive with some human tissues and food antigens, potentially leading to autoimmune responses.AIM To measure the immune reactivity of C. jejuni and C. jejuni cytolethal distending toxin(Cdt) antibodies with tissue and food antigens to examine their role in autoimmunities.METHODS Using enzyme-linked immunosorbent assay(ELISA) methodology, specific antibodies made against C. jejuni and C. jejuni Cdt were applied to a variety of microwell plates coated with 45 tissues and 180 food antigens. The resulting immunoreactivities were compared to reactions with control wells coated with human serum albumin(HSA) which were used as negative controls and with wells coated with C. jejuni lysate or C. jejuni Cdt which served as positive controls.RESULTS At 3 SD above the mean of control wells coated with HSA or 0.41 OD, the mouse monoclonal antibody made against C. jejuni showed moderate to high reactions with zonulin, somatotropin, acetylcholine receptor, β-amyloid and presenilin.This immune reaction was low with an additional 25 tissue antigens including asialoganglioside, and the same antibody did not react at all with another 15 tissue antigens. Examining the reaction between C. jejuni antibody and 180 food antigens, we found insignificant reactions with 163 foods but low to high immune reactions with 17 food antigens. Similarly, we examined the reaction of C. jejuni Cdt with the same tissues and food antigens. The strongest reactions were observed with zonulin, intrinsic factor and somatotropin. The reaction was moderate with 9 different tissue antigens including thyroid peroxidase, and reaction was low with another 10 different antigens, including neuronal antigens.The reaction of C. jejuni

关键词： Campylobacter jejuni Cytolethal distending toxin Tissue antigens Food antigens Autoimmune reactivities Cross-reactivity

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STUDIES ON SPECIFIC SEROLOGICAL antigens IN METACERCARIAE AND JUVENILES OF Paragoniums westermani AND ITS MONOCLONAL ANTIBODIES

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Science China Chemistry 1990年第2期33卷 178-187页

作者：蒋作君沈一平赵慰先 Nanjing Medical College Nanking 210005 PRC

The polyclonal antibodies to juveniles of Paragoniums westermani (PwJ-PcAbs) from sera of Wistar rats infected with Paragoniums westerrnani (P. w.)were purified by Sephadex G 200 chromatography. Next the shared serological antigens of P. w. metacercaria and juveniles (PwMJ-SAg) from the crude antigens of the metacercariae (M-NS-Ag) were purified with immuno-affinity chromatography on cyanogen bromide-activated cross-linked Sepharose 4B beads coupled withPwJ-PcAbs. PwMJ-SAg, agroup of glycoprotein molecules shown by the staining test, were specific serological antigens of P. w. metacercariae and juveniles, identified by the immunoabsorb test and immunoelectrophoresis. By SDSPAGE, PwMJ-SAg were fractionated to seven bands, including major bands A(27.SK) and Bi(19.5 K), the two major serological antigen molecules. 20 sera samples from the patients with the nonpulmonary type of P. w. paragonimiasis were detected using PwMJ-SAg and M-NS-Ag by Dot-ELISA, and the difference of sensitivity between two

关键词： paragonimiasis serological antigens monoclonal antibodies diagnosis.

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Detection of urinary antigens and their seroreactivity with serum of patients in Leishmania donovani infection

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Asian Pacific Journal of Tropical Medicine 2011年第5期4卷 367-370页

作者： Vinod Kumar Jalaj Kumar Gour Surabhi Bajpai Manish Mishra Rakesh Kumar Singh Molecular Immunology Laboratory Department of BiochemistryFaculty of ScienceBanaras Hindu UniversityVaranasi-221005India

Objective:To detect leishmanial antigens in pre and post treated urine of visceral leishmaniasis (VL) patients.Methods:Urine and serum sample from three VL patients were collected. Ammonium sulphate precipitation and purification of urine sample was done for proteins isolation.SDS PAGE of proteins was done followed by western blotting,with the patient’s pre and post treatment serum.Results:Eight proteins of molecular weights 17 kDa,25 kDa,28 kDa,42 kDa, 47 kDa,54 kDa,60 kDa and 85 kDa were detected in the urine of VL patients before treatment. After treatment with miltefosine,none of the above proteins was detected in urine samples.The western blot analysis with pre treatment serum confirmed the antigenicity of four urinary proteins of molecular weights 25 kDa,28 kDa,54 kDa and 60 kDa.The seropositivity with 25 kDa and 28 kDa antigens was negative with serum obtained after the completion of treatment.Conclusions:In the context to unavailability of a prognostic tool,urinary leishmanial antigens may offer a better choice and may also be useful as immunoprophylactic candidates.

关键词： Visceral leishmaniasis Urinary antigens Seroreactivity

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Hepatitis C virus antigens enzyme immunoassay for one-step diagnosis of hepatitis C virus coinfection in human immunodeficiency virus infected individuals

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World Journal of Hepatology 2019年第5期11卷 442-449页

作者： Ke-Qin Hu Wei Cui Susan D Rouster Kenneth E Sherman Division of GI/Hepatology University of CaliforniaIrvineSchool of MedicineOrangeCA 92868United States Division of Digestive Diseases University of Cincinnati College of MedicineCincinnatiOH 45267United States

BACKGROUND Current diagnosis of hepatitis C virus(HCV)infection requires two sequential steps:testing for anti-HCV followed by HCV RNA PCR to confirm viremia.We have developed a highly sensitive and specific HCV-antigens enzyme immunoassay(HCV-Ags EIA)for one-step diagnosis of viremic HCV infection.AIM To assess the clinical application of the HCV-Ags EIA in one-step diagnosis of viremic HCV infection in human immunodeficiency virus(HIV)-coinfected individuals.METHODS The study blindly tested HCV-Ags EIA for its performance in one-step diagnosing viremic HCV infection in 147 sera:10 without HCV or HIV infection;54 with viremic HCV monoinfection;38 with viremic HCV/HIV coinfection;and 45 with viremic HCV and non-viremic HIV coinfection.RESULTS Upon decoding,it was 100%accordance of HCV-Ags EIA to HCV infection status by HCV RNA PCR test.In five sera with HCV infection,HCV RNA was as low as 50-59 IU/mL,and four out of five tested positive for HCV-Ags EIA.Likewise,it was also 100%accordance of HCV-Ags EIA to HCV infection status by HCV RNA PCR in 83 sera with HCV and HIV coinfection,regardless if HIV infection was active or not.CONCLUSION The modified HCV-Ags EIA has a lower detection limit equivalent to serum HCV RNA levels of approximately 100 IU/mL.It is highly sensitive and specific in the setting of HIV coinfection,regardless of HIV infection status and CD4 count.These data support the clinical application of the HCV-Ags EIA in one-step diagnosis of HCV infection in HIV-infected individuals.

关键词： Hepatitis C virus Hepatitis C virus antigens Hepatitis C virus core antigen Hepatitis C virus diagnostic test Diagnostic assay Enzyme immunoassay

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Three-dimensional models of antigens with serodiagnostic potential for leprosy:An in silico study

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World Journal of Clinical Infectious Diseases 2023年第1期13卷 1-10页

作者： Bianca Luiza Melo de Assis Rafaela Viana Vieira Ian Theodoro Rudenco Gomes Palma Matheus Bertolini Coutinho Juliana de Moura Gabrielle Caroline Peiter Kádima Nayara Teixeira Campus Toledo Universidade Federal do ParanáToledo 85.919-899ParanáBrazil Departamento de Patologia Básica Universidade Federal do Paraná-Setor de Ciências BiológicasCuritiba 81.531-980ParanáBrazil Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular-Setor Palotina Universidade Federal do ParanáPalotina 85.950-000ParanáBrazil

BACKGROUND Leprosy is a disease caused by Mycobacterium leprae(M.leprae),an intracellular pathogen that has tropism and affects skin and nervous system cells.The disease has two forms of presentation:Paucibacillary and multibacillary,with different clinical and immunological manifestations.Unlike what occurs in the multibacillary form,the diagnostic tests for the paucibacillary form are nonspecific and not very sensitive,allowing the existence of infected individuals without treatment,which contributes to the spread of the pathogen in the population.To mitigate this contamination,more sensitive diagnostic tests capable of detecting paucibacillary patients are needed.AIM To predict the three-dimensional structure models of M.leprae antigens with serodiagnostic potential for leprosy.METHODS In this in silico study,satisfactory templates were selected in the Protein Data Bank(PDB)using Basic Local Alignment Search Tool to predict the structural templates of ML2038,ML0286,ML0050,and 85B antigens by comparative modeling.The templates were selected according to general criteria such as sequence identity,coverage,X-ray resolution,Global Model Quality Estimate value and phylogenetic relationship;Clustal X 2.1 software was used in this analysis.Molecular modeling was completed using the software Modeller 9v13.Visualization of the models was made using ViewerLite 4.2 and PyMol software,and analysis of the quality of the predicted models was performed using the QMEAN score and Z-score.Finally,the three-dimensional moels were validated using the MolProbity and Verify 3D platforms.RESULTS The three-dimensional structure models of ML2038,ML0286,ML0050,and 85B antigens of M.leprae were predicted using the templates PDB:3UOI(90.51%identity),PDB:3EKL(87.46%identity),PDB:3FAV(40.00%identity),and PDB:1F0N(85.21%identity),respectively.The QMEAN and Z-score values indicated the good quality of the structure models.These data refer to the monomeric units of antigens,since some of these antigens have quaternary structure.The validation

关键词： antigens Leprosy diagnosis Mycobacterium leprae Molecular modelling Serological test In silico study

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Neoantigens:promising targets for cancer therapy

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Signal Transduction and Targeted Therapy 2023年第2期8卷 446-483页

作者： Na Xie Guobo Shen Wei Gao Zhao Huang Canhua Huang Li Fu State Key Laboratory of Biotherapy and Cancer Center West China Hospitaland West China School of Basic Medical Sciences and Forensic MedicineSichuan Universityand Collaborative Innovation Center for BiotherapyChengdu610041China Clinical Genetics Laboratory Affiliated Hospital&Clinical Medical College of Chengdu UniversityChengdu610081China Guangdong Provincial Key Laboratory of Regional Immunity and Diseases Department of Pharmacology and International Cancer CenterShenzhen University Health Science CenterShenzhen518060GuangdongPeople’s Republic of China

Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for solid tumors.Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations,such as genomic mutation,dysregulated RNA splicing,disordered post-translational modification,and integrated viral open reading frames.Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance.The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies.Compared to tumor-associated antigens,the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies,and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses.The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies.This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens.We also explore their current status,inherent challenges,and clinical translation potential.

关键词： antigens alterations approval

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Expression of hepatitis B virus surface antigens induces defective gonad phenotypes in Caenorhabditis elegans

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World Journal of Virology 2017年第1期6卷 17-25页

作者： Yi-Yin Chen Li-Wei Lee Wei-Ning Hong Szecheng J Lo Department of Biomedical Science College of Medicine Chang Gung University Graduate Institute of Biomedical Science College of Medicine Chang Gung University

AIM To test whether a simple animal, Caenorhabditis elegans(C. elegans), can be used as an alternative model to study the interaction between hepatitis B virus antigens(HBs Ag) and host factors. METHODS Three plasmids that were able to express the large, middle and small forms of HBs Ags(LHBs Ag, MHBs Ag, and SHBs Ag, respectively) driven by a ubiquitous promoter(fib-1) and three that were able to express SHBs Ag driven by different tissue-specific promoters were constructed and microinjected into worms. The brood size, egglaying rate, and gonad development of transgenic worms were analyzed using microscopy. Levels of m RNA related to endoplasmic reticulum stress, enpl-1, hsp-4, pdi-3 and xbp-1, were determined using reverse transcription polymerase reaction(RT-PCRs) in three lines of transgenic worms and dithiothreitol(DTT)-treated wild-type worms. RESULTS Severe defects in egg-laying, decreases in brood size, and gonad retardation were observed in transgenic worms expressing SHBs Ag whereas moderate defects were observed in transgenic worms expressing LHBs Ag and MHBs Ag. RT-PCR analysis revealed that enpl-1, hsp-4 and pdi-3 transcripts were significantly elevated in worms expressing LHBs Ag and MHBs Ag and in wild-type worms pretreated with DTT. By contrast, only pdi-3 was increased in worms expressing SHBs Ag. To further determine which tissue expressing SHBs Ag could induce gonad retardation, we substituted the fib-1 promoter with three tissue-specific promoters(myo-2 for the pharynx, est-1 for the intestines and mec-7 for the neurons) and generated corresponding transgenic animals. Moderate defective phenotypes were observed in worms expressing SHBs Ag in the pharynx and intestines but not in worms expressing SHBs Ag in the neurons, suggesting that the secreted SHBs Ag may trigger a cross-talk signal between the digestive track and the gonad resulting in defective phenotypes. CONCLUSION Ectopic expression of three forms of HBs Ag that causes recognizable phenotypes in transgenic worms suggests that C. elega

关键词： Hepatitis B virus Caenorhabditis elegans Green fluorescence proteins Endoplasmic reticulum stress Gonad retardation Surface antigens

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