Characterizing head and neck tumor neoantigensand T cells: looking beyond the usual suspects

头颈肿瘤新抗原和 T 细胞的特征：超越通常的怀疑

• 批准号: 10359681
• 负责人: Joshua E Elias
• 金额: $ 46.74万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-05 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359681
• 关键词: Affect; Aftercare; Alleles; Antigen Presentation; Antigens; Bar Codes; Biological Models; Blood; Categories; Cell Count; Cell Line; Cell physiology; Cells; Cervical; Cisplatin; Clinical Trials; Cytometry; DNA sequencing; Data; Diagnosis; Disease; Disease-Free Survival; Evolution; Foundations; Functional disorder; Genome; Genomics; Goals; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Histocompatibility Antigens Class II; Human Papillomavirus; Human papilloma virus infection; Immune; Immune response; Immune system; Immunoglobulin Gene Rearrangement; Immunotherapeutic agent; Immunotherapy; In Vitro; Interferon Type II; Investigation; Knowledge; Lymphoma; Major Histocompatibility Complex; Malignant Epithelial Cell; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Methods; Mission; Monitor; Morbidity - disease rate; Mus; Mutate; Mutation; Mutation Analysis; National Institute of Dental and Craniofacial Research; Nucleic Acids; Operative Surgical Procedures; Patients; Peptide Fragments; Peptides; Phenotype; Population; Primary Neoplasm; Proteome; Proteomics; Public Health; Radiation; Radiation therapy; Reagent; Reporting; Research; Source; Stimulus; T cell receptor repertoire sequencing; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Technology; Testing; Therapeutic; Time; Tissues; Tumor Burden; Tumor Cell Line; Tumor-Infiltrating Lymphocytes; Uncertainty; United States National Institutes of Health; Virus; Work; Xenograft procedure; adaptive immune response; anti-PD1 antibodies; anti-PD1 therapy; base; body system; cancer therapy; cytokine; dark matter; effector T cell; engineered T cells; epigenomics; exhaustion; exome; exome sequencing; genomic locus; high dimensionality; high throughput screening; immune checkpoint; immune checkpoint blockade; improved; in vivo Model; melanoma; neoantigens; neoplastic cell; nonsynonymous mutation; novel strategies; patient derived xenograft model; personalized immunotherapy; pleiotropism; prevent; programmed cell death protein 1; protein expression; response; standard of care; success; targeted treatment; therapeutic vaccine; treatment response; tumor

PROJECT SUMMARY Immunotherapies targeting cancer-specific antigens (“neoantigens”) presented by Major Histocompatibility Complexes (MHC) have high potential for improving rates of long-term, disease-free survival. T cell engineer- ing technologies have found recent success in a limited number of clinical trials, and promise a new era of ef- fective treatments with greatly reduced adverse responses. Unlike melanoma, which neoantigen-targeting therapies have focused, head and neck squamous cell carcinomas (HNSCCs) have moderate-to-low tumor burdens. Thus they are less likely to present the same types of mutation-bearing antigens on their MHC mole- cules pursued by prior studies. However, new HNSCCs diagnoses are increasingly associated with human papilloma virus (HPV) infection, providing multiple types of alternative, therapeutically useful neoantigens that can be rationally targeted. A broad discovery platform compatible with multiple cancer neoantigen categories, including those induced by HPV, stands to extend T cell engineering approaches to HNSCC. The ultimate goal of this research is to define the broad range of HNSCC neoantigens a patient’s tumor presents on MHC, and the specific T cell receptors that recognize them. The main objectives of this proposal are (i) to compare HPV-dependent HNSCC antigens to other cancer-specific antigens; (ii) to test the extent to which neoantigen presentation can be induced by current HNSCC therapies; and (iii) to characterize the evolution of neoantigen- specific effector T cells and their T cell receptor repertoires in patients undergoing checkpoint blockade (PD1) therapy. In Aim 1, we will extend the approach we previously used to identify lymphoma-specific neoantigens derived from rearrangements of the immunoglobulin gene locus. By evaluating cell lines and primary HNSCC tumors with both DNA sequencing (exome and HPV-focused) and proteomic (protein expression, MHC antigen discovery) technologies, we will evaluate the extent to which HPV is a reliable source of neoantigens relative to other potential sources. De novo peptide sequencing methods we developed will allow us to discover neoanti- gens that would escape conventional proteomic search methods. In Aim 2, we will treat HNSCC cells with ra- diation, cisplatin, and interferon gamma in culture and in patient-derived mouse xenografts. We will monitor changes in neoantigen presentation induced by these treatments with the proteomic technologies used in Aim 1. In Aim 3, we will produce synthetic versions of prioritized neoantigens identified from our preliminary data and augmented by those revealed by Aims 1 and 2. We will assemble these with corresponding MHC mole- cules and in a multiplexed fashion, create panels of barcoded MHC tetramer panels. These will be used to profile T lymphocyte populations from HNSCC patients, from which clonal T cell receptors will be sequenced. Thus, our aims relieve the two major obstacles that currently limit neoantigen-targeting immunotherapies: they will provide high-throughput ways to identify HNSCC neoantigens and their cognate T cell receptors. This ap- proach should be broadly applicable to other cancers.

项目总结 主要组织相容性提出的针对癌症特异性抗原(“新抗原”)的免疫疗法 复合体(MHC)在提高长期无病存活率方面具有很高的潜力。T细胞工程师- ING技术最近在有限数量的临床试验中取得了成功，并有望开创一个新的Ef-Ef时代。 有效的治疗方法，大大减少了不良反应。与黑色素瘤不同的是，新抗原靶向 治疗方法有重点，头颈部鳞状细胞癌(HNSCC)有中到低的肿瘤 负担。因此，它们不太可能在其MHC分子上呈现相同类型的携带突变的抗原- 先前研究所追踪的猎物。然而，新的人类神经干细胞诊断越来越多地与人类 乳头状瘤病毒(HPV)感染，提供多种类型的替代、治疗有用的新抗原， 可以合理地锁定目标。与多种癌症新抗原类别兼容的广泛发现平台， 包括由HPV诱导的T细胞工程方法，有望将T细胞工程方法扩展到HNSCC。终极的 这项研究的目的是确定患者肿瘤在MHC上呈现的广泛的HNSCC新抗原， 以及识别它们的特定T细胞受体。这项建议的主要目的是(一)比较 HPV依赖的HNSCC抗原与其他癌症特异性抗原的相互作用；(Ii)检测新抗原 可由目前的HNSCC疗法诱导；以及(Iii)表征新抗原的进化- 检查点阻断(PD1)患者的特异性效应T细胞及其受体谱 心理治疗。在目标1中，我们将扩展以前用于识别淋巴瘤特异性新抗原的方法。 源于免疫球蛋白基因座的重排。通过评估细胞系和原代HNSCC 同时具有DNA测序(外显子组和HPV聚焦)和蛋白质组(蛋白质表达，MHC抗原)的肿瘤 发现)技术，我们将评估HPV是新抗原的可靠来源的程度相对于 其他潜在来源。我们开发的从头测序方法将使我们能够发现新的抗 可以逃脱传统蛋白质组搜索方法的基因。在目标2中，我们将用ra-Ra处理HNSCC细胞。 放射、顺铂和干扰素在培养和患者来源的小鼠异种移植中的作用。我们会监控 在AIM中使用蛋白质组技术的这些处理引起的新抗原提呈的变化 1.在目标3中，我们将制作根据我们的初步数据确定的优先新抗原的合成版本 并由目标1和目标2揭示的那些进行增强。我们将这些与相应的MHC摩尔组装在一起- 并以多路复用的方式创建条形码MHC四聚体面板。这些将被用来 HNSCC患者的T淋巴细胞亚群，克隆的T细胞受体将被测序。 因此，我们的目标是消除目前限制新抗原靶向免疫疗法的两大障碍：它们 将提供高通量的方法来鉴定HNSCC新抗原及其同源T细胞受体。这个AP- 该方法应广泛适用于其他癌症。

项目成果

An Integrated Genomic, Proteomic, and Immunopeptidomic Approach to Discover Treatment-Induced Neoantigens.

• DOI: 10.3389/fimmu.2021.662443
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Olsson N;Heberling ML;Zhang L;Jhunjhunwala S;Phung QT;Lin S;Anania VG;Lill JR;Elias JE
• 通讯作者: Elias JE

Humanized Mouse Models for the Advancement of Innate Lymphoid Cell-Based Cancer Immunotherapies.

• DOI: 10.3389/fimmu.2021.648580
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Horowitz NB;Mohammad I;Moreno-Nieves UY;Koliesnik I;Tran Q;Sunwoo JB
• 通讯作者: Sunwoo JB