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.

项目概要/摘要 癌细胞构建具有生物化学和生物物理属性的细胞糖萼，可以抵御攻击 目前，我们对癌细胞糖萼如何发挥作用的机制有了了解。 物理干扰效应细胞介导的杀伤的多种途径和单个步骤中的任何一种是高度 我们的总体假设是通过对糖萼有更好的物理理解。 抵抗免疫细胞攻击，我们可以更好地设计新的细胞工程策略来克服 我们的项目将特别关注糖萼介导的针对自然攻击的保护。 杀伤（NK）细胞在癌症免疫治疗领域备受关注。 针对肿瘤细胞的天然细胞毒活性，可以用嵌合抗原受体进一步改造 (CAR) 靶向特定的肿瘤抗原，因此，NK 细胞是过继细胞疗法的令人兴奋的候选者。 表面粘蛋白在癌症中高度过度表达，并作为糖萼的主要结构元件。 在本提案中，我们的目标是（1）确定粘蛋白的特定分子特性如何控制糖萼 结构，从而介导细胞对 NK 细胞攻击的抵抗；（2）通过以下方式确定具体机制： 哪些粘蛋白会物理性地破坏 NK 和 CAR-NK 攻击；以及 (3) 开发 NK 细胞工程策略以 克服粘蛋白屏障。 为了实现我们的目标，我们将采用我们实验室开发的最先进的成像方法 我们还将利用我们实验室的优势来表征糖萼的纳米级材料结构。 结合这些成像来设计糖萼的物理结构的专业知识和经过验证的工具。 和细胞工程策略与免疫细胞生物学中已建立的技术将实现新的特异性 关于糖萼在防止免疫细胞攻击方面的物理功能的假设 他们还将支持具有结构优化的 CAR 和工程 NK 细胞的设计和测试。 糖萼编辑酶可改善携带粘蛋白的癌细胞的消除。 过继细胞疗法在治疗顽固性癌症方面具有巨大的前景。 操纵和表征糖萼的物理结构的技术挑战，我们的物理 我们的项目将解决对癌细胞糖萼对过继细胞疗法产生耐药性的了解。 弥补知识差距并测试 NK 工程的新策略，如果成功，可以进一步开发 临床应用。