Harnessing anti-tumor macrophages for cancer therapy

利用抗肿瘤巨噬细胞进行癌症治疗

• 批准号: 8780388
• 负责人: Jennifer L. Guerriero
• 金额: $ 5.51万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780388
• 关键词: Affect; Apoptosis; Apoptotic; Biological Assay; Biology; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; Conditioned Culture Media; Data; Disseminated Malignant Neoplasm; Genes; Grant; Human; Immune; Immune system; In Vitro; Infection; Laboratories; Learning; Malignant Neoplasms; Measures; Mediating; Mission; Mitochondria; Mus; National Cancer Institute; Neoplasm Metastasis; Outcome; Paclitaxel; Phenotype; Population Heterogeneity; Property; Research Project Grants; Research Training; Resistance; Role; Signal Transduction; Testing; Therapeutic; Training; Tumor Promotion; University Hospitals; cancer cell; cancer therapy; chemotherapy; combat; density; fighting; improved; in vivo; macrophage; monocyte; neoplastic cell; novel; public health relevance; response; small molecule; tool; tumor; tumor growth; tumor immunology; tumor progression

DESCRIPTION (provided by applicant): While the immune system is perhaps best known for its ability to fight off infections, there is increasing evidence that the immune system can participate in combating cancer as well. If the immune system can be directed to fight cancer, it may prove to be both more effective and less toxic than chemotherapy. Immune cells such as tumor associated macrophages (TAMs) can represent up to 50% of a tumor mass and have been shown to contribute to chemoresistance. Macrophages are a heterogeneous population of cells and can broadly be divided into M1 macrophages, which are a potent defense against tumor cells, and M2 macrophages, which instead tend to support tumors. TAMs are generally considered to have M2 properties and promote tumor progression, metastasis, and resistance to chemotherapy. Clinically, a high tumor density of TAMs has been significantly associated with resistance to chemotherapy and a worse clinical outcome in the majority of human and mouse tumors. The pro-tumor role of TAMs has been well characterized but an understanding of how TAMs induce chemoresistance is lacking. Therefore, we propose to study the biology and mechanisms of how TAMs contribute to tumor promotion and chemoresistance utilizing a novel assay developed in our laboratory called BH3 profiling. BH3 profiling is used to determine whether a cell is relatively close to the threshold of cell death (relatively "primed" for death), r relatively far from the threshold ("unprimed"). We hypothesize that M1 macrophages will "prime" tumor cells, making them closer to the threshold of cell death and that M2 macrophages will induce an unprimed tumor cell phenotype. The long-term objectives proposed in this application are focused on activating components of the immune systems to activate a long-term anti-tumor response. This is in line with the mission of The National Cancer Institute, which among other things, supports research and training with respect to the treatment of cancer, specifically by providing training grants to research projects conducted by universities and hospitals. An important part of this proposal is that using what we learn, we will investigate strategies to convert pro-tumor M2 macrophages to anti-tumor M1 macrophages. Such a strategy would undermine the support that macrophages already in the tumor give to tumor cells and instead convert it to a coordinated attack on the tumor by the immune system. The results obtained from this project will have a considerable effect on future research projects in the field of tumor immunology as this project will provide evidence that activating macrophages during chemotherapy has great therapeutic implications. The unique and novel clinical focus of harnessing TAMs for anti-cancer therapy has the potential to have a considerable impact in cancer treatment including the possible eradication of primary and metastatic cancer.

描述（由申请人提供）：虽然免疫系统最出名的可能是其抵抗感染的能力，但越来越多的证据表明免疫系统也可以参与对抗癌症。如果可以引导免疫系统对抗癌症，那么它可能比化疗更有效且毒性更小。肿瘤相关巨噬细胞 (TAM) 等免疫细胞最多可占肿瘤质量的 50%，并且已被证明有助于化疗耐药。巨噬细胞是异质细胞群，大致可分为 M1 巨噬细胞和 M2 巨噬细胞，M1 巨噬细胞是对抗肿瘤细胞的有效防御剂，而 M2 巨噬细胞则倾向于支持肿瘤。 TAM 通常被认为具有 M2 特性并促进肿瘤进展、转移和化疗耐药。临床上，TAM 的高肿瘤密度与大多数人类和小鼠肿瘤的化疗耐药性以及较差的临床结果显着相关。 TAM 的促肿瘤作用已得到很好的表征，但对 TAM 如何诱导化疗耐药性的了解尚不清楚。因此，我们建议利用我们实验室开发的一种名为 BH3 分析的新型测定法来研究 TAM 如何促进肿瘤促进和化疗耐药性的生物学和机制。 BH3 分析用于确定细胞是否相对接近细胞死亡阈值（相对“准备好”死亡），是否相对远离阈值（“未准备好”）。我们假设 M1 巨噬细胞将“引发”肿瘤细胞，使它们更接近细胞死亡的阈值，而 M2 巨噬细胞将诱导未引发的肿瘤细胞表型。本申请提出的长期目标集中于激活免疫系统的组成部分以激活长期抗肿瘤反应。这符合国家癌症研究所的使命，其中包括支持癌症治疗方面的研究和培训，特别是为大学和医院开展的研究项目提供培训资助。该提案的一个重要部分是，利用我们所学到的知识，我们将研究将促肿瘤 M2 巨噬细胞转化为抗肿瘤 M1 巨噬细胞的策略。这种策略会破坏肿瘤中已有的巨噬细胞对肿瘤细胞的支持，并将其转化为免疫系统对肿瘤的协调攻击。该项目获得的结果将对肿瘤免疫学领域的未来研究项目产生相当大的影响，因为该项目将提供证据证明化疗期间激活巨噬细胞具有巨大的治疗意义。利用 TAM 进行抗癌治疗的独特而新颖的临床重点有可能对癌症治疗产生相当大的影响，包括可能根除原发性和转移性癌症。