Physical Resistance to Immune Cell Attack by the Cellular Glycocalyx

细胞糖萼对免疫细胞攻击的物理抵抗力

• 批准号: 10568002
• 负责人: Matthew J Paszek
• 金额: $ 45.45万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568002
• 关键词: Adoptive Cell Transfers; Attention; Biochemical; Biocompatible Coated Materials; Biophysics; Biopolymers; Cations; Cell Communication; Cell surface; Cells; Cellular biology; Cessation of life; Clinical; Cytolysis; Cytoplasmic Granules; Detection; Development; Dimensions; Effector Cell; Elements; Endowment; Engineering; Environmental Monitoring; Enzymes; Glycocalyx; Goals; Human; Image; Imaging Techniques; Immune; Immune Evasion; Immune mediated destruction; Immune system; Immunotherapy; Individual; Interference Microscopy; Intrinsic factor; Knowledge; Malignant Neoplasms; Measures; Mediating; Metabolic; Molecular; Mucins; Mucolytics; Natural Killer Cells; Oncogenic; Pathway interactions; Patient-Focused Outcomes; Pattern; Penetration; Physical Function; Polymers; Polysaccharides; Predisposition; Process; Property; Receptor Signaling; Refractory; Reporter; Reporting; Resistance; Role; Scanning; Signal Transduction; Structure; Surface; Techniques; Technology; Testing; Therapeutic; Thick; Tumor Antigens; cancer cell; cancer immunotherapy; cancer therapy; cell killing; cell type; cellular engineering; cellular microvillus; chimeric antigen receptor; clinical application; clinically relevant; cytotoxic; cytotoxicity; design; engineered NK cell; extracellular; glycosylation; imaging approach; immunoengineering; improved; innovation; insight; interest; mucinase; nanometer; nanoscale; neoplastic cell; overexpression; physical property; programs; receptor; superresolution imaging; tool; uptake

Project Summary/Abstract Cancer cells construct a cellular glycocalyx with biochemical and biophysical attributes that protect against attack by effector immune cells. Currently, our mechanistic understanding of how the cancer-cell glycocalyx may physically interfere with any of the multiple pathways and individual steps of effector-cell mediated killing is highly limited. Our overarching hypothesis is that by developing a better physical understanding of the glycocalyx in resistance to immune cell attack, we can better devise new cellular engineering strategies to overcome the glycocalyx barrier. Our project will specifically focus on glycocalyx-mediated protection against attack by Natural Killer (NK) cells, which are attracting significant attention in the field of cancer immunotherapy. NK cells possess natural cytotoxic activity against tumor cells and can be further engineered with a chimeric antigen receptor (CAR) to target a specific tumor antigen. As such, NK cells are exciting candidates for adoptive cell therapy. Cell surface mucins are highly overexpressed in cancer and serve as primary structural elements of the glycocalyx. In this proposal, our aims are to (1) determine how specific molecular properties of mucins govern the glycocalyx structure and thereby mediate cellular resistance to NK-cell attack; (2) identify the specific mechanisms through which mucins physically disrupt NK and CAR-NK attack; and (3) develop NK cellular engineering strategies to overcome the mucin barrier. To complete our aims, we will employ state-of-the-art imaging approaches that our lab has developed for characterizing the nanoscale material structure of the glycocalyx. We also will take advantage of our lab’s expertise and validated tools for engineering the physical structure of the glycocalyx. Combining these imaging and cellular engineering strategies with established techniques in immune cell biology will enable new specific hypotheses regarding the physical functioning of the glycocalyx in protection against immune cell attack to be tested. They will also support the design and testing of engineered NK cells with structure-optimized CARs and glycocalyx-editing enzymes for improved elimination of mucin-bearing cancer cells. Adoptive cell therapy has tremendous promise for treating otherwise recalcitrant cancers. In part due to the technical challenges of manipulating and characterizing the physical structure of the glycocalyx, our physical understanding of the cancer-cell glycocalyx in resistance to adoptive cell therapy is poor. Our project will address this knowledge gap and test new strategies for NK engineering that, if successful, can be further developed for clinical applications.

项目摘要/摘要 癌细胞构建具有生物化学和生物物理特性的细胞糖基化产物，以保护其免受攻击。 通过效应器免疫细胞。目前，我们对癌细胞糖基化反应的机械性理解 物理上干扰效应细胞介导的杀伤的多个途径和单个步骤中的任何一个是高度 有限的。我们最重要的假设是，通过更好地了解体内的糖基化反应 抵抗免疫细胞的攻击，我们可以更好地设计新的细胞工程策略来克服 糖萼屏障。我们的项目将专门专注于糖基化反应介导的防御天然病毒的攻击。 杀伤(NK)细胞，在癌症免疫治疗领域引起了极大的关注。NK细胞拥有 对肿瘤细胞的天然细胞毒活性，并可进一步利用嵌合抗原受体进行工程改造 (CAR)靶向特定的肿瘤抗原。因此，NK细胞是过继细胞治疗的令人兴奋的候选细胞。细胞 表面粘蛋白在癌症中高度过度表达，是糖萼的主要结构元素。 在这项建议中，我们的目标是(1)确定粘蛋白的特定分子属性如何支配糖萼 结构，从而调节细胞对NK细胞攻击的抵抗力；(2)通过 哪些粘蛋白在物理上破坏NK和CAR-NK攻击；以及(3)开发NK细胞工程策略以 克服粘蛋白障碍。 为了实现我们的目标，我们将使用我们实验室为其开发的最先进的成像方法 表征糖萼的纳米级材料结构。我们还将利用我们实验室的 专业知识和经过验证的工具，用于设计糖萼的物理结构。结合这些成像 细胞工程策略和免疫细胞生物学的成熟技术将使新的特定 关于糖萼在保护免疫细胞攻击中的物理功能的假设是 测试过。他们还将支持设计和测试具有结构优化的汽车和 用于改善粘蛋白癌细胞清除的糖萼编辑酶。 采用细胞疗法在治疗顽固性癌症方面有着巨大的前景。部分原因是 操纵和表征糖萼的物理结构的技术挑战，我们的物理 对过继细胞治疗耐药的肿瘤细胞糖基化反应的了解很差。我们的项目将解决 这一知识差距和测试NK工程的新战略，如果成功，可以进一步开发用于 临床应用。