权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Glycocalyx Targeting and Augmenting Cellular Immunity in Lung Cancer

糖萼靶向并增强肺癌细胞免疫

基本信息

批准号：
10650162
负责人：
MARK M FUSTER
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650162
关键词：
Affect Antigen Presentation Antigen-Presenting Cells Antigens Antisense Oligonucleotides Automobile Driving Bone Marrow CD8-Positive T-Lymphocytes Cancer Model Carcinoma Cell Surface Receptors Cells Cellular Immunity Characteristics Complement Cytolysis Cytotoxic T-Lymphocytes Dendritic Cells Disease remission Effector Cell Endowment Excision Family Genetic Genetic Induction Glycocalyx Goals Heparitin Sulfate Human Immune Immune Targeting Immune system Infiltration Ligation Lung Lung Neoplasms Lymphatic Lymphatic Endothelial Cells Lymphatic Endothelium Malignant neoplasm of lung Marrow Measures Mediating Methods Modeling Mus Mutation Pathway interactions Physiologic pulse Polymers Polysaccharides Process Proliferating Proteoglycan Reporting Repression Sialic Acids Specificity Structure Sulfate Surface System T cell response T-Cell Proliferation T-Cell Receptor T-Lymphocyte TCR Activation Technology Testing Therapeutic Time Transgenic Organisms Tumor Antigens Tumor Burden Tumor Immunity Work anti-cancer autoimmune toxicity cancer therapy checkpoint therapy cytotoxic CD8 T cells design exhaustion immune checkpoint immune checkpoint blockade improved in vivo inhibitor insight lung Carcinoma mouse model neoantigens novel pre-clinical response sensitizing antigen sialylation sugar tumor tumor growth tumor microenvironment

项目摘要

In lung cancer, tumor immunity is fueled by antigen presenting cells (APCs). We found that targeting glycans on dendritic immune cells (DCs, as “professional” APCs) boosts CD8+ T cell influx and tumor cytolysis, likely via augmented presentation of tumor antigens (Ag) on DCs. Augmenting continuous tumor Ag sensing via this “endogenous” tumor microenvironment (TME) system may improve the specificity and magnitude of anti-tumor immunity. In Merit work, we discovered how genetic targeting of unique DC glycans boosts anti-tumor T cell responses, at least in part via Ag presentation mechanisms. We here build on initial insights. An advantage to facilitating this process is that the “epicenter” for tumor Ag recognition (i.e., MHC/Ag - T-cell receptor axis) may respond to dynamic Ag changes (including new mutations) to sustain tumor-cytotoxic CD8+ T cells in the TME. Current immune-checkpoint therapy in advanced-stage lung cancer shows durable remissions that are limited (<25%), and autoimmune toxicity poses serious challenges. We hypothesize that altering glycan fine structure (proteoglycan under-sulfation or sialic acid inhibition) on the APC glycocalyx will boost Ag presentation and augment anti-tumor T cell responses. To study this, with novel inhibitor strategies, we propose Aims as follows: Study how targeting glycocalyx composition on key APCs from the TME augments anti-tumor T cell responses, and test how genetic under-sulfation and under-sialylation of the lung APC glycocalyx affects tumor growth inhibition and specific anti-tumor T-cell responses, including in vivo T cell proliferation and infiltration (Aim 1). This will involve altering the fine structure of heparan sulfate or inhibiting sialic acid glycans that repress APC effector functions in the TME. We will examine CD8+ T cell proliferation, activation, and tumor cytolysis in the setting of APC-targeted glycan inhibition in tumor models with Ag-responsive T cell reporting systems. Studies will include characterizing how mutation affects tolerance/exhaustion signatures in DCs purified from the lung TME. We also study lymphatic glycan targeting to transform lymphatic endothelium into a novel APC platform. Discover mechanisms by which glycan structural changes promote spatial and temporal display of MHC/Ag on tumor DCs, and study how this augments engagement with the T cell receptor (TcR) using model Ag and transgenic T cells (Aim 2). We will study how DC glycocalyx mutations in the fine structure of heparan sulfate and sialic acid affect Ag presentation by tumor-Ag sensitized DCs or ex-vivo marrow DCs pulsed with model Ag. We will also study how such mutations on model Ag systems affect TcR interactions with DC MHC-I/Ag using novel proximity ligation technology. Beyond these approaches, we will measure MHC-I/Ag internalization on the DC surface in the setting of glycocalyx targeting strategies. We will include parallel studies on tumor lymphatic endothelial cells as unique APCs in Ag-presentation/TcR engagement studies using similar methods. We will develop glycan-specific inhibitors that augment APC-mediated tumor-kill responses and tumor antigen responsiveness when applied to mouse as well as human lung carcinomas, and complement this with studies of real-time tumor regression using inhibitors in spontaneous lung cancer models (Aim 3). We will study anti- tumor T-cell responses using adoptive therapeutic approaches with glycan-targeted DCs, including antisense oligonucleotide (ASO) approaches to inhibit tumor-APC glycan fine structure, and examine anti-tumor CD8+ T cell responses in ASO targeted spontaneous lung cancer models. We include immune technology to study T cell responses to unique model tumor antigens as well as non-biased responses to high neo-antigen tumor loads in the system. We will also assess how APC glycocalyx targeting affects immune checkpoint pathways in tumor CD8+ T cells, and study how pairing inhibitors with low-level checkpoint blockade potentiates responses.

在肺癌中，肿瘤免疫是由抗原呈递细胞（APC）激发的。我们发现针对聚糖树突状免疫细胞（DCs，作为“专业”APC）可能会促进CD 8 + T细胞流入和肿瘤细胞溶解，通过增强DC上肿瘤抗原（Ag）的呈递。通过这种方法增强连续的肿瘤Ag感测 “内源性”肿瘤微环境（TME）系统可提高抗肿瘤的特异性和幅度免疫力在Merit的工作中，我们发现了独特DC聚糖的遗传靶向如何增强抗肿瘤T细胞反应，至少部分通过Ag呈递机制。我们在此以初步的见解为基础。的优点促进这一过程的是肿瘤Ag识别的“中心”（即，MHC/Ag-T细胞受体轴）可能响应动态Ag变化（包括新突变），以维持TME中的肿瘤细胞毒性CD 8 + T细胞。目前晚期肺癌的免疫检查点治疗显示出有限的持久缓解（<25%），自身免疫毒性带来了严重的挑战。我们假设改变聚糖的精细结构（蛋白聚糖硫酸化不足或唾液酸抑制）将促进Ag呈递，增强抗肿瘤T细胞应答。为了研究这一点，我们提出了新的抑制剂策略，目标如下：研究来自TME的关键APC上的靶向糖萼组合物如何增强抗肿瘤T细胞应答，并测试肺APC糖萼的遗传性硫酸化不足和唾液酸化不足如何影响肿瘤生长抑制和特异性抗肿瘤T细胞应答，包括体内T细胞增殖和浸润（目的1）。这将涉及改变硫酸乙酰肝素的精细结构或抑制抑制APC的唾液酸聚糖 TME中的效应器功能。我们将研究CD 8 + T细胞的增殖、活化和肿瘤细胞溶解。在具有Ag应答性T细胞报告系统的肿瘤模型中设置APC靶向聚糖抑制。研究将包括表征突变如何影响从肺中纯化的DC中的耐受性/耗竭特征 TME。我们还研究了淋巴聚糖靶向将淋巴内皮转化为新的APC平台。发现聚糖结构变化促进MHC/Ag在细胞表面的时空展示的机制。肿瘤DC，并研究这如何增强与T细胞受体（TcR）的接合，使用模型Ag和转基因T细胞（Aim 2）。我们将研究DC糖萼突变如何在硫酸乙酰肝素的精细结构中起作用和唾液酸影响肿瘤抗原致敏的DC或体外模型致敏的骨髓DC的抗原提呈 AG.我们还将研究模型Ag系统上的这种突变如何影响TcR与DC MHC-I/Ag的相互作用使用新的邻位连接技术。除了这些方法，我们将测量MHC-I/Ag内化在糖萼靶向策略的设置中在DC表面上。我们将纳入肿瘤的平行研究淋巴管内皮细胞作为独特的APC在Ag呈递/TcR接合研究中使用类似的方法。我们将开发聚糖特异性抑制剂，增强APC介导的肿瘤杀伤反应和肿瘤抗原当应用于小鼠以及人肺癌时，在自发性肺癌模型中使用抑制剂进行实时肿瘤消退（目的3）。我们将研究反- 使用聚糖靶向DC的过继治疗方法的肿瘤T细胞应答，包括反义寡核苷酸，寡核苷酸（阿索）方法来抑制肿瘤-APC聚糖精细结构，并检查抗肿瘤CD 8 + T细胞在阿索靶向的自发性肺癌模型中的细胞应答。我们将免疫技术纳入研究T 对独特模型肿瘤抗原的细胞应答以及对高新抗原肿瘤抗原的非偏倚应答系统中的负载。我们还将评估APC糖萼靶向如何影响免疫检查点途径，肿瘤CD 8 + T细胞，并研究如何配对抑制剂与低水平的检查点阻断增强反应。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Time Domains of Hypoxia Responses and -Omics Insights.

DOI：
10.3389/fphys.2022.885295
发表时间：
2022
期刊：
Frontiers in physiology
影响因子：
4
作者：
通讯作者：

IL-33/ST2 receptor-dependent signaling in the development of pulmonary hypertension in Sugen/hypoxia mice.

DOI：
10.14814/phy2.15185
发表时间：
2022-03
期刊：
Physiological reports
影响因子：
2.5
作者：
Indralingam CS;Gutierrez-Gonzalez AK;Johns SC;Tsui T;Cannon DT;Fuster MM;Bigby TD;Jennings PA;Breen EC
通讯作者：
Breen EC

Glycocalyx transduces membrane leak in brain tumor cells exposed to sharp magnetic pulsing.