Restoring the Immunogenicity of Head and Neck Cancer

恢复头颈癌的免疫原性

• 批准号: 10732281
• 负责人: Yu Leo Lei
• 金额: $ 56.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732281
• 关键词: Address; Agonist; Antigen-Presenting Cells; Beds; Biochemical; Carcinogens; Cells; Clinical; Competence; Complex; Cross-Priming; Cytoplasm; DNA; DNA Repair; DNA Replication Induction; Dependence; Dinucleoside Phosphates; Effectiveness; Effector Cell; Endoplasmic Reticulum; Engineering; Epithelial Cells; Funding; Gene Activation; Generations; Genes; Genetic Engineering; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hematopoietic; Human; Human papillomavirus 16; Immune; Immune Tolerance; Immunity; Immunotherapy; Implant; Individual; Interferon Activation; Interferon Type I; Interferons; Intraepithelial Neoplasia; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Membrane; Metabolic; Methods; Modeling; Molecular; Mus; Mutation; Myeloid Cells; Nanodelivery; Nanotechnology; Oncogenes; Pathway interactions; Patients; Performance; Periodicity; Phosphorylation; Phosphorylation Site; Physiological; Prevention; Preventive; Production; RNA; Recurrence; Resistance; Resolution; Role; Shapes; Signal Transduction; Solid Neoplasm; Specimen; Stains; Stimulator of Interferon Genes; Sting Injury; System; T-Cell Receptor; T-Lymphocyte Subsets; T-cell inflamed; Therapeutic; Time; Tissue Microarray; Translating; Tumor Antigens; Tumor-infiltrating immune cells; Unresectable; analysis pipeline; cancer cell; checkpoint receptors; effector T cell; fitness; gene induction; gene translocation; immune cell infiltrate; immune checkpoint; immune checkpoint blockade; immunogenicity; improved; innate immune sensing; innovation; irradiation; nanoparticle; nanoparticle delivery; novel; oral cavity epithelium; programs; public health relevance; replication stress; response; sensor; single cell technology; synergism; trafficking; tumor; γδ T cells

PROJECT SUMMARY Immune checkpoint receptor blockade (ICB) has been approved recently for the treatment of metastatic, unresectable, or recurrent head and neck squamous cell carcinoma (HNC) in the first-line setting. Multiple priming strategies have entered into trials, aiming to turn cold HNCs, which account for about 85% of the cases, into T-cell inflamed hot tumors and expand the pool of patients who can benefit from immunotherapy. Mechanistically, many priming strategies activate innate immune sensors to launch the production of type-I interferons (IFN-I) by cancer cells and myeloid cells. The activation of IFN-I and its target genes promotes antigen-presenting cell (APC) and effector cell trafficking to the tumor bed and enhances APC cross-priming efficiency. A central converging point of the current priming approaches is an adaptor molecule located at the endoplasmic reticulum and its associated membranes, stimulator of interferon genes (STING). Lead cold tumor sensitization treatments, such as irradiation, inhibition of DNA damage repair, induction of DNA replication stress, and STING agonists all engage the STING pathway, further validating the promise of STING-priming in restoring the immunogenicity of cancers. However, recent trials of STING agonists showed a high resistance rate in patients with solid tumors, even in combination with ICB. The mechanism of HNC resistance to STING priming is poorly understood, and few strategies are available to overcome cancer resistance to innate immune sensing. The long-term goal of this program is to establish the biochemical and metabolic regulatory network of HNC immunogenicity and improve HNC prevention and immunotherapy by releasing the checkpoints on innate immune sensors. During the initial funding period, we have uncovered driver oncogenes that disable the STING pathway and promote immune tolerance, we have engineered the first-generation nanoparticles to improve the intracellular delivery of STING agonists, we have streamlined our single-cell immune analysis pipelines to render intra-lesional immune landscape as a function of time. Recently, we discovered a new pathway that suppresses HNC initiation through IFN-I activation. This renewal project will parlay our previous accomplishments and our recent discovery into a cohesive program that addresses the mechanisms of HNC resistance to STING stimulation and optimizes the engineering of a new generation of nanoparticles for innate immune priming in hosts insensitive to free STING agonists. To support this goal, we have established comprehensive modeling for HNC initiation and response plasticity to STING stimulation, including carcinogen-induced models, implantable models, and genetically engineered models. Resistance to STING stimulation disqualifies a spectrum of cold cancer priming strategies. This renewal project will uncover a pivotal molecular mechanism underpinning the fitness of innate immune sensors and optimize robust nanotechnology overcoming cancer resistance in individuals insensitive to STING stimulation.

项目摘要 免疫检查点受体阻断剂（ICB）最近已被批准用于治疗 转移性、不可切除或复发性头颈部鳞状细胞癌（HNC）的一线治疗。 多种启动策略已进入试验阶段，旨在将冷HNC转化为冷HNC，其占约85%， 的情况下，进入T细胞发炎的热肿瘤，并扩大池的病人谁可以受益于 免疫疗法从机制上讲，许多引发策略激活先天免疫传感器以启动免疫系统。 由癌细胞和骨髓细胞产生I型干扰素（IFN-I）。IFN-Ⅰ的激活及其作用靶点 基因促进抗原呈递细胞（APC）和效应细胞运输到肿瘤床，并增强APC 交叉启动效率当前引发方法的一个中心汇合点是衔接分子 位于内质网及其相关膜，干扰素基因刺激因子（STING）。 铅冷致敏肿瘤的治疗方法，如照射、抑制DNA损伤修复、诱导 DNA复制应激和STING激动剂都参与STING途径，进一步验证了 STING-引发恢复癌症的免疫原性。然而，最近的STING激动剂试验显示， 实体瘤患者的耐药率高，即使与ICB联合使用。HNC的机理 对STING引发的抗性知之甚少，几乎没有克服癌症的策略 抵抗先天免疫感应。该计划的长期目标是建立生物化学和 HNC免疫原性的代谢调控网络，并通过以下方式改善HNC预防和免疫治疗： 释放先天免疫传感器上的检查点在最初的融资期间，我们发现 驱动癌基因，使STING途径失效并促进免疫耐受，我们已经设计了 第一代纳米颗粒，以改善STING激动剂的细胞内递送，我们已经简化了我们的 单细胞免疫分析管道，以呈现作为时间函数的病灶内免疫景观。 最近，我们发现了一个新的途径，抑制HNC启动通过IFN-I激活。此续订 该项目将利用我们以前的成就和我们最近的发现成为一个有凝聚力的计划， 解决了HNC对STING刺激的抗性机制，并优化了一种新的 在对游离STING激动剂不敏感的宿主中产生用于先天免疫引发的纳米颗粒。支持 为此，我们建立了HNC启动和对STING反应可塑性的综合模型 刺激，包括致癌物诱导的模型，植入模型，和基因工程模型。 对STING刺激的抗性使一系列冷癌引发策略不合格。这个重建项目 将揭示支撑先天免疫传感器适应性的关键分子机制，并优化 强大的纳米技术克服了对STING刺激不敏感的个体的癌症抗性。

项目成果

Antibiotic nanoparticles boost antitumor immunity.

抗生素纳米颗粒可增强抗肿瘤免疫力。

• DOI: 10.1038/s41587-023-02046-6
• 发表时间: 2023
• 期刊: Nature biotechnology
• 影响因子: 46.9
• 作者: Han,Kai;Cho,YoungSeok;Moon,JamesJ
• 通讯作者: Moon,JamesJ

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response.

• DOI: 10.1080/2162402x.2018.1494112
• 发表时间: 2018
• 期刊: Oncoimmunology
• 影响因子: 7.2
• 作者: Kansy BA;Shayan G;Jie HB;Gibson SP;Lei YL;Brandau S;Lang S;Schmitt NC;Ding F;Lin Y;Ferris RL
• 通讯作者: Ferris RL

Supervised capacity preserving mapping: a clustering guided visualization method for scRNA-seq data.

保存映射的监督能力：用于SCRNA-SEQ数据的聚类指导性可视化方法。

• DOI: 10.1093/bioinformatics/btac131
• 发表时间: 2022-04-28
• 期刊: Bioinformatics (Oxford, England)

Single-Cell Multimodal Prediction via Transformers

• DOI: 10.1145/3583780.3615061
• 发表时间: 2023-03
• 期刊: ArXiv
• 作者: Wenzhuo Tang;Haifang Wen;Renming Liu;Jiayuan Ding;Wei Jin;Yuying Xie;Hui Liu;Jiliang Tang

IL-10 Dampens an IL-17-Mediated Periodontitis-Associated Inflammatory Network.

• DOI: 10.4049/jimmunol.1900532
• 发表时间: 2020-04-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Sun L;Girnary M;Wang L;Jiao Y;Zeng E;Mercer K;Zhang J;Marchesan JT;Yu N;Moss K;Lei YL;Offenbacher S;Zhang S
• 通讯作者: Zhang S