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Neoantigen cancer vaccines:a new star on the horizon

Cancer Biology & Medicine 2024年第4期21卷 274-311页

作者： Xiaoling Li Jian You Liping Hong Weijiang Liu Peng Guo Xishan Hao Cell Biotechnology Laboratory Tianjin Cancer Hospital Airport HospitalTianjin 300308China National Clinical Research Center for Cancer Tianjin 300060China Haihe Laboratory of Synthetic Biology Tianjin 300090China Department of Thoracic Oncology Tianjin Cancer Hospital Airport HospitalTianjin 300308China Department of Thoracic Oncology Surgery Tianjin Medical University Cancer Institute&HospitalTianjin 300060China Tianjin Medical University Cancer Institute&Hospital Tianjin 300060China

Immunotherapy represents a promising strategy for cancer treatment that utilizes immune cells or drugs to activate the patient's own immune system and eliminate cancer cells.One of the most exciting advances within this field is the targeting of neoantigens,which are peptides derived from non-synonymous somatic mutations that are found exclusively within cancer cells and absent in normal cells.Although neoantigen-based therapeutic vaccines have not received approval for standard cancer treatment,early clinical trials have yielded encouraging outcomes as standalone monotherapy or when combined with checkpoint inhibitors.Progress made in high-throughput sequencing and bioinformatics have greatly facilitated the precise and efficient identification of neoantigens.Consequently,personalized neoantigen-based vaccines tailored to each patient have been developed that are capable of eliciting a robust and long-lasting immune response which effectively eliminates tumors and prevents recurrences.This review provides a concise overview consolidating the latest clinical advances in neoantigen-based therapeutic vaccines,and also discusses challenges and future perspectives for this innovative approach,particularly emphasizing the potential of neoantigen-based therapeutic vaccines to enhance clinical efficacy against advanced solid tumors.

关键词： Immunotherapy neoantigen cancer vaccine solid tumors high-throughput sequencing bioinformatics PDOs AI hla TCR

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hla-A、-B功能表位错配对血液病患者血小板输注效果的影响分析

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中国输血杂志 2024年第6期37卷 673-677页

作者：俞露贺云蕾何意文李双月陈春销邓刚宁波市中心血站输血研究所浙江宁波315000 宁波大学附属第一医院输血科宁波大学医学院附属人民医院血液科

目的探究hla抗原(human leukocyte antigen,hla)功能表位错配(epitope mismatch,EM)对血液病患者血小板输注有效性的影响。方法对血小板供者和2021年6月—2023年6月间申请血小板血清学交叉配型和hla基因配型的血液病患者,用PCR-SBT法进... 详细信息

目的探究hla抗原(human leukocyte antigen,hla)功能表位错配(epitope mismatch,EM)对血液病患者血小板输注有效性的影响。方法对血小板供者和2021年6月—2023年6月间申请血小板血清学交叉配型和hla基因配型的血液病患者,用PCR-SBT法进行hla基因分型,hla基因配型是基于CREG的原则为患者选择供者。对患者临床血小板输注资料进行回顾性分析,使用hla Matchmaker 4.0软件分析供体-受体hla EM信息,并从国际hla表位注册网站(www.Epregistry.***.br)中查询相关hla功能表位(Eplets)的表达量、基因分布等信息。评价hla EM对血小板输注效果的影响。结果血液病患者血小板的输注有效性与患者性别、年龄无关,而与患者的血小板配型策略相关。当hla EM总数在20以下时,供受者hla EM总数越低的分组,其血小板输注有效率越高(χ^(2)=19.311,P=0.001),24 h血小板计数(Plt)增量校正值(CCI)平均数也越高(F=7.737,Phla EM总数与24 h CCI实际值呈负相关(Rho=-0.322,Phla-A(17.6%)或-B位点(64.7%)独有,或者是hla-A和-B位点共享(17.6%);且其表达量可能是高表达(58.8%),或者是中等表达(41.2%)。结论hla EM的总数是影响血小板输注有效性的重要因素;发现若干与血小板的输注有效性相关的hla Eplets。

关键词：血小板输注无效抗原表位错配 hla 表位

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破解“输注无效”的基因密钥 008

破解“输注无效”的基因密钥

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浙江日报

作者：林晓晖罗建根

血液是“生命之河”，供养着人体全部器官的正常运转。具有止血、凝血功能的血小板，就成为临床医疗救治中不可替代的重要资源。日前，全国血小板管理与应用大会在浙江召开，主题为“血小板全流程精准输血的现代化先行探索”。会上，... 详细信息

血液是“生命之河”，供养着人体全部器官的正常运转。具有止血、凝血功能的血小板，就成为临床医疗救治中不可替代的重要资源。日前，全国血小板管理与应用大会在浙江召开，主题为“血小板全流程精准输血的现代化先行探索”。会上，浙江省血液中心发布打造血小板基因库的最?

关键词：血液中心输血医学 hla 血小板计数输注无效

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Correlative CD4 and CD8 T-cell immunodominance in humans and mice:Implications for preclinical testing

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Cellular & Molecular Immunology 2023年第11期20卷 1328-1338页

作者： Tertuliano Alves Pereira Neto John Sidney Alba Grifoni Alessandro Sette Center for Infectious Disease and Vaccine Research La Jolla Institute for Immunology(LJI)La JollaCA92037USA Department of Medicine Division of Infectious Diseases and Global Public HealthUniversity of CaliforniaSan DiegoLa JollaCA92037USA

Antigen-specific T-cell recognition is restricted by Major Histocompatibility Complex(MHC)molecules,and differences between CD4 and CD8 immunogenicity in humans and animal species used in preclinical vaccine testing are yet to be fully understood.In this study,we addressed this matter by analyzing experimentally identified epitopes based on published data curated in the Immune Epitopes DataBase(IEDB)database.We first analyzed SARS-CoV-2 spike(S)and nucleoprotein(N),which are two common targets of the immune response and well studied in both human and mouse systems.We observed a weak but statistically significant correlation between human and H-2^(b)mouse T-cell responses(CD8 S specific(r=0.206,p=1.37×10^(−13));CD4 S specific(r=0.118,p=2.63×10^(−5))and N specific(r=0.179,p=2.55×10^(−4))).Due to intrinsic differences in MHC molecules across species,we also investigated the association between the immunodominance of common Human Leukocyte Antigen(hla)alleles for which hla transgenic mice are available,namely,A*02:01,B*07:02,DRB1*01:01,and DRB1*04:01,and found higher significant correlations for both CD8 and CD4(maximum r=0.702,p=1.36×10^(−31)and r=0.594,p=3.04−122,respectively).Our results further indicated that some regions are commonly immunogenic between humans and mice(either H-2^(b)or hla transgenic)but that others are human specific.Finally,we noted a significant correlation between CD8 and CD4 S-(r=0.258,p=7.33×10^(21))and N-specific(r=0.369,p=2.43×10^(14))responses,suggesting that discrete protein subregions can be simultaneously recognized by T cells.These findings were confirmed in other viral systems,providing general guidance for the use of murine models to test T-cell immunogenicity of viral antigens destined for human use.

关键词： T cells SARS-CoV-2 Vaccine Animal testing hla

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Rare peptide anchors of hla class I alleles contribute to the COVID-19 disease severity and T cell memory

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Biosafety and Health 2023年第6期5卷 355-362页

作者： Xin Wang Jie Zhang Peipei Guo Yuanyuan Guo Xiaonan Yang Maoshun Liu Danni Zhang Yaxin Guo Jianbo Zhan Kun Cai Jikin Zhou Shaobo Dong Jun Liu Department of Epidemiology School of Public HealthCheeloo College of MedicineShandong UniversityJinan 250012China NHC Key Laboratory of Biosafety Research Unit of Adaptive Evolution and Control of Emerging VirusesChinese Academy of Medical SciencesNational Institute for Viral Disease Control and PreventionChinese Center for Disease Control and Prevention(China CDC)Beijing 102206China Beijing Key Laboratory of Emerging Infectious Diseases Institute of Infectious DiseasesBeijing Ditan HospitalCapital Medical UniversityBeijing 100015China Beijing Institute of Infectious Diseases Beijing 100015China National Center for Infectious Diseases Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China School of Laboratory Medicine and Life Sciences Wenzhou Medical UniversityWenzhou 325035China Hubei Provincial Center for Disease Control and Prevention Wuhan 430079China Shijiazhuang Fifth Hospital Shijiazhuang 050011China Macheng Center for Disease Control and Prevention Huanggang 438300China

Understanding how human leukocyte antigen(hla)polymorphism affects both the susceptibility and severity of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection will help to identify individuals at higher risk to better manage and prioritize vaccination at the clinical level and explain the differences in epidemic trends in different regions at the epidemiological level.This study compared the frequencies of hla class I alleles(hla-A,B)in 214 coronavirus disease 2019(COVID-19)patients with different disease severity and 35 healthy controls and analyzed the correlations between specific hla alleles and disease severity and T cell memory.The results showed no significant difference in hla allele frequencies between COVID-19 patients and healthy controls(P>0.05).The allele hla-B*13:02 was significantly correlated with the disease severity of COVID-19 patients(P=0.006).After adjustment for age and disease severity,the T cell responses of COVID-19 convalescents with the allele hla-B*40:01 may be lower at six months(P=0.044)and 12 months(P=0.069).Moreover,these results may be due to their rare peptide anchors by analyzing the binding peptide motifs of these hla alleles.The study may be valuable for investigating the potential association of specific hla alleles with SARS-CoV-2 infection.

关键词： SARS-CoV-2 COVID-19 hla Susceptibility Disease severity

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运用二代测序技术确认PCR-SSOP法检出的hla罕见等位基因

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中国实验血液学杂志 2023年第1期31卷 203-208页

作者：钟显信巫望达全湛柔高素青深圳市中医院医学检验科广东深圳518033 深圳市血液中心输血医学研究所广东深圳518020

目的:确认PCR-序列特异性寡核苷酸探针(SSOP)法检出的4例磁珠探针hla基因分型结果格局异常和3例模棱两可结果样本的hla真实基因型。方法:对hla高分辨组织配型血样采用PCR-SSOP法检出的4例磁珠探针hla基因分型结果格局异常和3例模棱两可... 详细信息

目的:确认PCR-序列特异性寡核苷酸探针(SSOP)法检出的4例磁珠探针hla基因分型结果格局异常和3例模棱两可结果样本的hla真实基因型。方法:对hla高分辨组织配型血样采用PCR-SSOP法检出的4例磁珠探针hla基因分型结果格局异常和3例模棱两可结果进一步采用PCR-直接测序分型(SBT)技术和二代测序(NGS)技术复检确认。结果:采用PCR-SSOP方法检出4例磁珠探针hla基因分型结果格局异常的样本,加做SBT及NGS两种方法复检后结果显示,样本1的hla-A分型结果与已知基因型不完全匹配,NGS分析显示,该等位基因与同源性最接近的等位基因A*31:01:02:01在第2外显子154位G>A变异,导致28位编码氨基酸由缬氨酸变为蛋氨酸(p.Val28Met),样本2的hla-C结果为C*03:119, 06:02,样本3的hla-C结果为C*03:03, 07:137,样本4的hla-B结果为B*55:02,55:12。采用PCR-SSOP方法检出3例模棱两可结果样本,加做SBT及NGS两种方法复检后结果显示,样本5的hla-B结果为B*15:58, 38:02,样本6的hla-DRB1结果为DRB1*04:05, 14:101,样本7的hla-DQB1结果为DQB1*03:34,05:02。其中等位基因C*03:119、C*07:137和DRB1*14:101均未收录于中国造血干细胞捐献者资料库的常见及确认等位基因(CWD)表2.4版本。结论:PCR-SSOP法磁珠探针hla基因分型结果格局异常提示可能为hla罕见等位基因或新等位基因,需要测序验证。

关键词： hla 等位基因 PCR-序列特异性寡核苷酸探针 PCR-直接测序分型二代测序

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Modulation of hla Expression in Human Cytomegalovirus Immune Evasion

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Cellular & Molecular Immunology 2007年第2期4卷 91-98页

作者： Aifen Lin Huihui Xu Weihua Yan Medical Research Center Wenzhou Medical College Affiliated Taizhou Hospital of Zhejiang Province Linhai Zhejiang 317000 China

Human cytomegalovirus （hCMV） has evolved multiple mechanisms to escape the host immune recognition and innate or adaptive immune responses. Among them, hCMV has developed strategies to modulate the expression and/or function of human leukocyte antigens （hlas）, including by encoding series of infection stage-dependent hCMV proteins to detain and destroy the expression of hla molecules on the surface of infected cells. This disturbs the antigen presentation and processing, by encoding MHC class I homologues or selective up-regulation of particular hla class I molecules binding to NK cell inhibitory receptors, and by encoding specific ligand antagonists to interfere with NK cell activating receptors. Here we discussed the molecular mechanisms utilized by the hCMV to alter the formation, transportation and expression of hla antigens on the infected cell surface. The knowledge about hCMV modulating hla expression could benefit us to further understand the pathogenesis of viral diseases and may eventually develop novel effective immunotherapies to counteract viral infections and viral associated diseases.

关键词： hla human cytomegalovirus NK cell T lymphocyte

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Safety of in vitro amplified hla-haploidentical donor immune cell infusions for childhood malignancies

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Chinese Journal of Cancer 2013年第12期32卷 661-666页

作者： Fei Zhang Xiao-Fei Sun Yong-Qiang Li Zi-Jun Zhen Hai-Xia Zheng Jia Zhu Qi-Jing Wang Su-Ying Lu Jia He Juan Wang Ke Pan Rui-Qing Cai Yan Chen De-Sheng Weng Fei-Fei Sun Jian-Chuan Xia State Key Laboratory of Oncology in South China Department of Pediatric Oncology Department of Biotherapy Sun Yat-sen University Cancer Center

In vitro amplified human leukocyte antigen(hla)-haploidentical donor immune cell infusion(HDICI)is not commonly used in children.Therefore,our study sought to evaluate its safety for treating childhood malignancies.Between September 2011 and September 2012,12 patients with childhood malignancies underwent HDICI in Sun Yat-sen University Cancer Center.The median patient age was 5.1 years(range,1.7-8.4 years).Of the 12 patients,9 had high-risk neuroblastoma(NB)[7 showed complete response(CR),1 showed partial response(PR),and 1 had progressive disease(PD)after multi-modal therapies],and 3 had Epstein-Barr virus(EBV)-positive lymphoproliferative disease(EBV-LPD).The 12 patients underwent a total of 92 HDICIs at a mean dose of 1.6×108immune cells/kg body weight:71 infusions with natural killer(NK)cells,8 with cytokine-induced killer(CIK)cells,and 13 with cascade primed immune cells(CAPRIs);83 infusions with immune cells from the mothers,whereas 9 with cells from the fathers.Twenty cases(21.7%)of fever,including 6 cases(6.5%)accompanied with chills and 1(1.1%)with febrile convulsion,occurred during infusions and were alleviated after symptomatic treatments.Five cases(5.4%)of mild emotion changes were reported.No other adverse events occurred during and after the completion of HDIDIs.Neither acute nor chronic graft versus host disease(GVHD)was observed following HDICIs.After a median of 5.0 months(range,1.0-11.5 months)of follow-up,the 2 NB patients with PR and PD developed PD during HDICIs.Of the other 7 NB patients in CR,2 relapsed in the sixth month of HDICIs,and 5 maintained CR with disease-free survival(DFS)ranging from 4.5 to 11.5 months(median,7.2months).One EBV-LPD patient achieved PR,whereas 2 had stable disease(SD).Our results show that HDICI is a safe immunotherapy for childhood malignancies,thus warranting further studies.

关键词：免疫细胞恶性肿瘤体外扩增安全性 hla 儿童人类白细胞抗原移植物抗宿主病

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Preparation and Characterization of hla-A*0201 Tetramer Loaded with IE-1_(316-324) Antigenic Peptide of Human Cytomegalovirus

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Cellular & Molecular Immunology 2006年第5期3卷 367-371页

作者： Lihui Xu Qingbing Zha Hong Sun Qiantao Jia Fengyao Li Xianhui He Institute of Tissue Transplantation and Immunology College of Life Science and Technology Jinan University Guangzhou 510632 China Institute of Bioengineering College of Life Science and Technology Jinan University Guangzhou 510632 China Clinical Experimental Center of the First Affiliated Hospital linan University Guangzhou 510632 China Institute of Tissue Transplantation and Immunology College of Life Science and Technology Jinan University 601 Huangpu Dadao West Guangzhou 510632 China

Major histocompatibility complex （MHC） class I tetramer technology has become the central technique for analyzing antigen-specific CD8^＋ T cell responses and it has been widely used to explore the differentiation and formation of memory CD8^＋ T cells. Previously, a simplified and efficient procedure for preparing high quality hla-A＊0201 tetramers has been established in our lab and the tetramers loaded with HCMV peptide pp6549s.50a has been successfully applied to investigate HCMV-specific CD8^＋ T cells in Chinese populations. Using similar procedure we reported here the construction of hla-A＊0201 tetramer loaded with another dominant epitope derived from immediate early （IE）-1 316.324 （VLEETSVML, VLE） of HCMV （A2-VLE） and characterization of this tetramer. After A2-VLE monomer was prepared and purified, its tetramer was then formed at a yield of 83%. The optimized amount of A2-VLE tetramer for staining 100 μl whole blood was 0.5 μg with incubation at 4℃ for 1 h. Furthermore, the dissociation constant of the tetramer binding to the specific CD8^＋ T cells of one hla-A2^＋ donor was estimated to be 32.7 nmol/L, which is markedly higher than that of MHC monomer. The construction of A2-VLE tetramer provides an alternative choice for investigating HCMV-specific CD8^＋ T cell responses and will deepen our understanding of the differentiation and formation of HCMV-specific memory CD8^＋ T cells. Cellular ＆ Molecular Immunology.

关键词： hla tetramer cytomegalovirus immediate early-1 dissociation constant

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Carcinogenesis of nasopharyngeal carcinoma:an alternate hypothetical mechanism

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Chinese Journal of Cancer 2016年第1期35卷 26-34页

作者： Sharon Shuxian Poh Melvin Lee Kiang Chua Joseph T.S.Wee Division of Radiation Oncology National Cancer Centre11 Hospital Drive Duke-NUS Graduate Medical School

Current proposed mechanisms implicate both early and latent Epstein-Barr virus(EBV)infection in the carcinogenic cascade,whereas epidemiological studies have always associated nasopharyngeal carcinoma(NPC)with early childhood EBV infection and with chronic ear,nose,and sinus conditions.Moreover,most patients with NPC present with IgA antibody titers to EBV capsid antigen(VCA-lgA),which can precede actual tumor presentation by several years.If early childhood EBV infection indeed constitutes a key event in NPC carcinogenesis,one would have to explain the inability to detect the virus in normal nasopharyngeal epithelium of patients at a high risk for EBV infection.It is perhaps possible that EBV resides within the salivary glands,instead of the epithelium,during latency.This claim is indirectly supported by observations that the East Asian phenotype shares the characteristics of an increased susceptibility to NPC and immature salivary gland morphogenesis,the latter of which is influenced by the association of salivary gland morphogenesis with an evolutionary variant of the human ectodysplasin receptor gene(EDAR),EDARV370A.Whether the immature salivary gland represents a more favorable nidus for EBV is uncertain,but in patients with infectious mononucleosis,EBV has been isolated in this anatomical organ.The presence of EBV-induced lymphoepitheliomas in the salivary glands and lungs further addresses the possibility of submucosal spread of the virus.Adding to the fact that the fossa of Rosen Muller contains a transformative zone active only in the first decade of life,one might be tempted to speculate the possibility of an alternative carcinogenic cascade for NPC that is perhaps not dissimilar to the model of human papillomavirus and cervical cancer.

关键词： Nasopharyngeal carcinoma, Carcinogenesis, Epstein-Barr virus, Transformation zone, Toll-like receptor 8(TLR8), EDAR gene, hla

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