Restoring the Immunogenicity of Head and Neck Cancer
恢复头颈癌的免疫原性
基本信息
- 批准号:10732281
- 负责人:
- 金额:$ 56.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAgonistAntigen-Presenting CellsBedsBiochemicalCarcinogensCellsClinicalCompetenceComplexCross-PrimingCytoplasmDNADNA RepairDNA Replication InductionDependenceDinucleoside PhosphatesEffectivenessEffector CellEndoplasmic ReticulumEngineeringEpithelial CellsFundingGene ActivationGenerationsGenesGenetic EngineeringGoalsHead and Neck CancerHead and Neck Squamous Cell CarcinomaHematopoieticHumanHuman papillomavirus 16ImmuneImmune ToleranceImmunityImmunotherapyImplantIndividualInterferon ActivationInterferon Type IInterferonsIntraepithelial NeoplasiaLeadMalignant Epithelial CellMalignant NeoplasmsMediatingMembraneMetabolicMethodsModelingMolecularMusMutationMyeloid CellsNanodeliveryNanotechnologyOncogenesPathway interactionsPatientsPerformancePeriodicityPhosphorylationPhosphorylation SitePhysiologicalPreventionPreventiveProductionRNARecurrenceResistanceResolutionRoleShapesSignal TransductionSolid NeoplasmSpecimenStainsStimulator of Interferon GenesSting InjurySystemT-Cell ReceptorT-Lymphocyte SubsetsT-cell inflamedTherapeuticTimeTissue MicroarrayTranslatingTumor AntigensTumor-infiltrating immune cellsUnresectableanalysis pipelinecancer cellcheckpoint receptorseffector T cellfitnessgene inductiongene translocationimmune cell infiltrateimmune checkpointimmune checkpoint blockadeimmunogenicityimprovedinnate immune sensinginnovationirradiationnanoparticlenanoparticle deliverynoveloral cavity epitheliumprogramspublic health relevancereplication stressresponsesensorsingle cell technologysynergismtraffickingtumorγδ T cells
项目摘要
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
期刊论文数量(18)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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:
- 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:
- 影响因子:0
- 作者:
- 通讯作者:
Single-Cell Multimodal Prediction via Transformers
- DOI:10.1145/3583780.3615061
- 发表时间:2023-03
- 期刊:
- 影响因子:0
- 作者:Wenzhuo Tang;Haifang Wen;Renming Liu;Jiayuan Ding;Wei Jin;Yuying Xie;Hui Liu;Jiliang Tang
- 通讯作者: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:
- 影响因子:0
- 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
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Yu Leo Lei其他文献
IL-1α Mediated Suppressive Myeloid Function in Head and Neck Cancer
IL-1α 介导的头颈癌抑制性骨髓功能
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Hulya F. Taner;Wang Gong;Kohei Okuyama;Luke Proses;Wanqing Cheng;Jung Kuczura;Sashider Rajesh;Yuying Xie;Yu Leo Lei - 通讯作者:
Yu Leo Lei
Localized intratumoral delivery of immunomodulators for oral cancer and oral potentially malignant disorders
免疫调节剂口腔癌和口腔潜在恶性疾病的局部肿瘤内输送
- DOI:
10.1016/j.oraloncology.2024.106986 - 发表时间:
2024-11-01 - 期刊:
- 影响因子:3.900
- 作者:
Nourhan I. Hussein;Andrea H. Molina;Gemalene M. Sunga;Moran Amit;Yu Leo Lei;Xiao Zhao;Jeffrey D. Hartgerink;Andrew G. Sikora;Simon Young - 通讯作者:
Simon Young
Resolving an Immune Tolerogenic Niche at the Earliest Phase of Oral Cancer Initiation
在口腔癌发生的最早阶段解决免疫耐受性生态位
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Hulya Taner;Wang Gong;Luke Broses;Kohei Okuyama;Wanqing Cheng;Jung Kuczura;Sashider Rajesh;Yee Sun Tan;Shadmehr Demehri;Jianwen Que;Yuying Xie;Yu Leo Lei - 通讯作者:
Yu Leo Lei
Sox2-driven Epithelial Transformation Promotes IL1-mediated Peripheral Immune Tolerance
Sox2 驱动的上皮转化促进 IL1 介导的外周免疫耐受
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Hulya F. Taner;Wang Gong;Kohei Okuyama;Luke Broses;Wanqing Cheng;Jung Kuczura;Sashider Rajesh;Yuying Xie;Yu Leo Lei - 通讯作者:
Yu Leo Lei
BATF2 suppresses cancer initiation by promoting γδ T-cell-mediated immunity
BATF2 通过促进 γδ T 细胞介导的免疫来抑制癌症发生
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Wang Gong;Hulya Taner;Yuesong Wu;Wanqing Cheng;Kohei Okuyama;Zaiye Li;Shadmehr Demehri;Felipe Nor;Deepak Nagrath;Steven B Chinn;Christopher R Donnelly;James J Moon;Yuying Xie;Yu Leo Lei - 通讯作者:
Yu Leo Lei
Yu Leo Lei的其他文献
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{{ truncateString('Yu Leo Lei', 18)}}的其他基金
Engineered Nano-formulations for STING Activation
用于 STING 激活的工程纳米制剂
- 批准号:
10539415 - 财政年份:2022
- 资助金额:
$ 56.19万 - 项目类别:
Engineered Nano-formulations for STING Activation
用于 STING 激活的工程纳米制剂
- 批准号:
10661091 - 财政年份:2022
- 资助金额:
$ 56.19万 - 项目类别:
New Engineering Strategy for Harnessing Immune System against Head and Neck Cancer
利用免疫系统对抗头颈癌的新工程策略
- 批准号:
10316349 - 财政年份:2021
- 资助金额:
$ 56.19万 - 项目类别:
New Engineering Strategy for Harnessing Immune System against Head and Neck Cancer
利用免疫系统对抗头颈癌的新工程策略
- 批准号:
10615115 - 财政年份:2021
- 资助金额:
$ 56.19万 - 项目类别:
New Engineering Strategy for Harnessing Immune System against Head and Neck Cancer
利用免疫系统对抗头颈癌的新工程策略
- 批准号:
10434134 - 财政年份:2021
- 资助金额:
$ 56.19万 - 项目类别:
Develop a Therapeutic Nano-vaccine against Head and Neck Cancer
开发针对头颈癌的治疗性纳米疫苗
- 批准号:
10372999 - 财政年份:2018
- 资助金额:
$ 56.19万 - 项目类别:
Develop a Therapeutic Nano-vaccine against Head and Neck Cancer
开发针对头颈癌的治疗性纳米疫苗
- 批准号:
9895433 - 财政年份:2018
- 资助金额:
$ 56.19万 - 项目类别:
Development of a Prognostic Compound Immunoscore for Head and Neck Cancer
头颈癌预后复合免疫评分的开发
- 批准号:
9766266 - 财政年份:2018
- 资助金额:
$ 56.19万 - 项目类别:
Autophagy-promoting NLRX1-TUFM complex and cancer cell resistance to cetuximab
促进自噬的NLRX1-TUFM复合物和癌细胞对西妥昔单抗的耐药性
- 批准号:
8923237 - 财政年份:2014
- 资助金额:
$ 56.19万 - 项目类别:
Autophagy-promoting NLRX1-TUFM complex and cancer cell resistance to cetuximab
促进自噬的NLRX1-TUFM复合物和癌细胞对西妥昔单抗的耐药性
- 批准号:
9464986 - 财政年份:2014
- 资助金额:
$ 56.19万 - 项目类别:
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