Harnessing anti-tumor macrophages for cancer therapy

描述(申请人提供)：虽然免疫系统可能以其抵御感染的能力而闻名，但越来越多的证据表明，免疫系统也可以参与抗击癌症。如果免疫系统能够被引导去抗击癌症，它可能会被证明比化疗更有效，毒性也更小。免疫细胞，如肿瘤相关巨噬细胞(TAMs)，可以代表高达50%的肿瘤质量，并已被证明有助于化疗耐药。巨噬细胞是一个异质的细胞群体，大致可分为M1巨噬细胞和M2巨噬细胞，M1巨噬细胞对肿瘤细胞具有强大的防御能力，而M2巨噬细胞则倾向于支持肿瘤。TAMs通常被认为具有M2特性，并促进肿瘤的进展、转移和对化疗的耐药性。临床上，在大多数人和小鼠肿瘤中，高肿瘤密度与化疗耐药和较差的临床结果显著相关。TAMs的促肿瘤作用已经得到了很好的表征，但对TAMs如何诱导化疗耐药缺乏了解。因此，我们建议利用我们实验室开发的一种名为BH3图谱的新方法来研究TAMs如何促进肿瘤和化疗耐药的生物学和机制。BH3图谱被用来确定一个细胞是否相对接近细胞死亡的阈值(相对“准备好”死亡)，r相对远离阈值(“未准备好”)。我们假设M1巨噬细胞将“启动”肿瘤细胞，使它们更接近细胞死亡的阈值，而M2巨噬细胞将诱导未启动的肿瘤细胞表型。在这项申请中提出的长期目标是专注于激活免疫系统的组件以激活长期的抗肿瘤反应。这与国家癌症研究所的使命相一致，该研究所除其他外，支持癌症治疗方面的研究和培训，特别是通过向大学和医院开展的研究项目提供培训赠款。这项提议的一个重要部分是，利用我们所学到的知识，我们将研究将亲肿瘤的M2巨噬细胞转化为抗肿瘤的M1巨噬细胞的策略。这样的策略将破坏肿瘤中已有的巨噬细胞对肿瘤细胞的支持，而是将其转化为免疫系统对肿瘤的协同攻击。该项目的研究结果将对未来肿瘤免疫学领域的研究项目产生相当大的影响，因为该项目将提供证据，证明在化疗过程中激活巨噬细胞具有重大的治疗意义。利用TAMs进行抗癌治疗的独特和新颖的临床焦点有可能对癌症治疗产生相当大的影响，包括可能根除原发和转移癌症。

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.