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: 8595768
• 负责人: Jennifer L. Guerriero
• 金额: $ 5.22万
• 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/8595768
• 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）：虽然免疫系统也许以其抵抗感染的能力而闻名，但越来越多的证据表明免疫系统也可以参与对抗癌症。如果可以指示免疫系统与癌症作斗争，则可能被证明比化学疗法更有效和毒性更小。免疫细胞（如肿瘤相关的巨噬细胞（TAM））可以代表多达50％的肿瘤肿块，并已被证明有助于化学耐药性。巨噬细胞是一种异质细胞种群，可以大致分为M1巨噬细胞，这些巨噬细胞是针对肿瘤细胞的有效防御，而M2巨噬细胞则倾向于支持肿瘤。通常认为TAM具有M2特性，并促进肿瘤进展，转移和对化学疗法的耐药性。在临床上，TAM的高肿瘤密度与对化疗的耐药性显着相关，并且大多数人类和小鼠肿瘤的临床结局较差。 TAMS的亲肿瘤作用已得到很好的特征，但了解TAM缺乏诱导化学抗性的理解。因此，我们建议利用在我们的实验室中开发的一种名为BH3分析的新测定法研究TAM如何促进肿瘤促进和化学抗性的生物学和机制。 BH3分析用于确定一个细胞是否相对接近细胞死亡的阈值（相对“启动”死亡），r距离阈值相对较远（“未置换”）。我们假设M1巨噬细胞将“素巨噬细胞”“原始”肿瘤细胞，使其更接近细胞死亡的阈值，并且M2巨噬细胞会诱导未爆发的肿瘤细胞表型。本应用程序中提出的长期目标集中在激活免疫系统的成分，以激活长期的抗肿瘤反应。这符合国家癌症研究所的使命，该研究所的使命是支持癌症治疗的研究和培训，特别是通过向大学和医院进行的研究项目提供培训补助金。该提案的一个重要部分是，使用我们所学的知识，我们将研究将亲肿瘤M2巨噬细胞转换为抗肿瘤M1巨噬细胞的策略。这种策略会破坏肿瘤中巨噬细胞对肿瘤细胞的支持，而将其转化为免疫系统对肿瘤的协调攻击。从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表明，在化学疗法期间激活巨噬细胞具有很大的治疗意义。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，包括可能消除原发性和转移性癌症。