Identifying and engaging a universal adjuvant for breaking macrophage immune tolerance in cancer

识别并使用一种通用佐剂来破坏癌症中的巨噬细胞免疫耐受

• 批准号: 10297776
• 负责人: Mingye Feng
• 金额: $ 43.15万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-08 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297776
• 关键词: Adjuvant; Antineoplastic Agents; B-Lymphocytes; Biochemical; Bioinformatics; Biological; Biological Assay; Blocking Antibodies; CD47 gene; CSF1R gene; Cancer Model; Cell Communication; Cell surface; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Development; Dose; Eating; Engraftment; Excision; FDA approved; Hematopoietic Neoplasms; Human; Immune; Immune Evasion; Immune Tolerance; Immune response; Immunologic Surveillance; Immunologics; Immunotherapy; In Vitro; Investigation; Lead; Macrophage Activation; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Molecular; Natural Killer Cells; Paclitaxel; Phagocytes; Phagocytosis; Phenotype; Play; Pre-Clinical Model; Predisposition; Primary Neoplasm; Process; Regimen; Regulation; Research Proposals; Role; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; T-Lymphocyte; Therapeutic; Toxic effect; Translations; Treatment Efficacy; Tumor Escape; Tumor-associated macrophages; anti-cancer; base; bench to bedside; cancer cell; cancer immunotherapy; cancer therapy; cancer type; chemotherapy; cytotoxicity; design; high throughput screening; immune checkpoint; improved; in vivo; innovation; invention; macrophage; mouse model; neoplastic cell; new combination therapies; novel; novel therapeutics; pre-clinical; receptor; response; screening; small molecule; targeted agent; treatment response; tumor

Project Summary/Abstract The ability of cancer cells to evade immunosurveillance is one of the hallmarks of cancer. Understanding the mechanisms by which T, B and NK cells detect and attack cancer cells and developing approaches to break tumor immune tolerance have revolutionized the treatment of various human cancers. Macrophages are the major components of primary tumors and metastatic sites, and emerging studies have demonstrated that the escape from macrophage immunosurveillance is a critical immune evasion mechanism of cancer cells. Recent paradigm-shifting discoveries have begun to reveal that inducing macrophage-mediated cancer cell recognition and phagocytosis, a process termed programmed cell removal (PrCR), is crucial to tumor surveillance and elimination. A “don’t eat me” signal CD47 has been identified to be upregulated on a variety of malignant hematopoietic and solid tumor cells, and blockade of CD47 enables the susceptibility of cancer cells to PrCR. Recent progress in clinical trials demonstrated significant therapeutic potential of restoring PrCR as a promising cancer immunotherapy. While inducing PrCR holds considerable promise in treating multiple types of cancers, its underlying mechanisms remain unclear, which have hindered the development of PrCR-based therapy to achieve its maximal efficacy. The overall objective of this research proposal is to develop strategies to promote macrophage-mediated cancer surveillance and elimination by breaking macrophage tolerance, and to determine the efficacy and mechanisms of such strategies in PrCR-based cancer immunotherapy. The proposed studies focus on identifying and engaging adjuvants to augment the anticancer efficacy of PrCR-based therapy, and dissecting the molecular mechanisms of PrCR activation and macrophage-cancer cell interaction. Aim1 is to examine the roles of PrCR adjuvants in enhancing the efficacy of CD47-blocking antibodies, determine to what extent the adjuvants break macrophage immune tolerance to augment PrCR-based therapy, and decipher the composition and phenotype of tumor-associated macrophages upon the treatment of the adjuvants, with in vitro and in vivo preclinical cancer models. Aim2 is focused on understanding the molecular mechanisms of the adjuvants in augmenting the efficacy of PrCR-based therapy, by identifying the molecular machinery involved in cancer cell phagocytosis and the function and regulation of PrCR immune checkpoints in mediating macrophage- cancer cell interaction. A combination of in vitro and in vivo cell biological, biochemical, bioinformatic, and immunological methods will be used for the proposed studies. The investigation of the underlying mechanism of PrCR activation and regulation will enable a better understanding of the basic principles of cancer development and inspire the invention of more effective cancer immunotherapies. Successful completion of this study will lead to the identification of novel functional components mediating cancer immune evasion and will immediately provide novel therapeutic opportunities for a variety of cancers.

项目摘要/摘要 癌细胞逃避免疫监视的能力是癌症的标志之一。了解 t，b和nk细胞检测和攻击癌细胞的机制以及开发破裂的方法 肿瘤免疫耐受性彻底改变了对各种人类癌症的治疗。巨噬细胞是 原发性肿瘤和转移性部位的主要成分以及新兴研究表明 逃避巨噬细胞免疫监视是癌细胞的关键免疫避免机制。最近的 范式转移发现已经开始表明，诱导的巨噬细胞介导的癌细胞识别 吞噬作用是一种称为程序性细胞去除（PRCR）的过程，对肿瘤监测至关重要 消除。 “不要吃我”信号CD47已被确定为各种恶性 造血和实体瘤细胞，以及CD47的阻断使癌细胞对PRCR的敏感性。 临床试验的最新进展表明，恢复PRCR的显着治疗潜力 癌症免疫疗法。虽然诱导的PRCR在治疗多种类型的癌症方面具有很大的希望，但 它的基本机制尚不清楚，这阻碍了基于PRCR的治疗的发展 实现其最大效率。该研究建议的总体目标是制定策略来促进 巨噬细胞介导的癌症监测和进化，通过破坏巨噬细胞的耐受性，并确定 基于PRCR的癌症免疫疗法中此类策略的效率和机制。提出的研究 专注于识别和参与调节器，以提高基于PRCR的治疗的抗癌效率，并 解剖PRCR激活和巨噬细胞细胞相互作用的分子机制。 AIM1是 检查PRCR调节器在增强CD47阻滞抗体效率方面的作用，确定什么 范围的探索者破坏了巨噬细胞免疫对基于PRCR的治疗的耐受性，并破译了 在体外，肿瘤相关巨噬细胞的组成和表型与体外 和体内临床前癌模型。 AIM2专注于理解分子机制 通过确定涉及的分子机械来提高基于PRCR的治疗效率的调节器 癌细胞的吞噬作用以及PRCR免疫检查点的功能和调节，介导巨噬细胞 - 癌细胞相互作用。体外和体内细胞生物学，生化，生化和 免疫学方法将用于拟议的研究。研究的基本机制 PRCR激活和调节将使人们能够更好地了解癌症发展的基本原理 并激发更有效的癌症免疫疗法的事故。这项研究的成功完成将领导 鉴定介导癌症免疫进化的新型功能成分，并将立即 为各种取消提供新颖的治疗机会。