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.

项目概要 免疫检查点受体阻断（ICB）最近已被批准用于治疗 一线治疗中的转移性、不可切除性或复发性头颈鳞状细胞癌 (HNC)。 多种启动策略已进入试验阶段，旨在扭转约占85%的冷HNC 将病例转化为 T 细胞发炎的热肿瘤，并扩大可从中受益的患者群体 免疫疗法。从机制上讲，许多启动策略都会激活先天免疫传感器来启动 癌细胞和骨髓细胞产生 I 型干扰素 (IFN-I)。 IFN-I的激活及其靶点 基因促进抗原呈递细胞 (APC) 和效应细胞运输至肿瘤床并增强 APC 交叉启动效率。当前启动方法的中心汇聚点是接头分子 位于内质网及其相关膜，干扰素基因 (STING) 刺激剂。 铅冷肿瘤致敏治疗，如照射、抑制DNA损伤修复、诱导 DNA 复制应激和 STING 激动剂均参与 STING 通路，进一步验证了 STING 引发恢复癌症的免疫原性。然而，最近的 STING 激动剂试验表明 即使与ICB联合使用，实体瘤患者的耐药率也很高。 HNC的机制 人们对 STING 引发的抗性知之甚少，并且很少有策略可以用来克服癌症 对先天免疫感应的抵抗。该计划的长期目标是建立生化和 HNC 免疫原性的代谢调节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。在最初的资助期间，我们发现 驱动癌基因禁用 STING 通路并促进免疫耐受，我们设计了 第一代纳米颗粒可改善 STING 激动剂的细胞内递送，我们简化了我们的 单细胞免疫分析管道将病灶内免疫景观呈现为时间的函数。 最近，我们发现了一种通过 IFN-I 激活来抑制 HNC 启动的新途径。此次续订 项目将把我们以前的成就和我们最近的发现整合成一个有凝聚力的计划， 解决 HNC 对 STING 刺激的抵抗机制并优化新的工程 生成纳米颗粒，用于在对游离 STING 激动剂不敏感的宿主中启动先天免疫。支持 为了实现这一目标，我们建立了 HNC 启动和对 STING 响应可塑性的综合模型 刺激，包括致癌物诱导模型、植入模型和基因工程模型。 对 STING 刺激的抵抗使一系列冷癌症启动策略失效。本次更新改造项目 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抵抗力。

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.

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

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

The functions of autophagy at the tumour-immune interface.

自噬在肿瘤免疫界面的功能

• DOI: 10.1111/jcmm.16331
• 发表时间: 2021-03
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Luo X;Qiu Y;Dinesh P;Gong W;Jiang L;Feng X;Li J;Jiang Y;Lei YL;Chen Q
• 通讯作者: Chen Q