Harnessing anti-tumor macrophages for cancer therapy

描述（由申请人提供）：虽然免疫系统可能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。如果免疫系统可以被引导来对抗癌症，它可能被证明比化疗更有效，毒性更小。免疫细胞如肿瘤相关巨噬细胞（TAM）可占肿瘤质量的50%，并已显示有助于化疗耐药性。巨噬细胞是一种异质性细胞群，可以大致分为M1巨噬细胞和M2巨噬细胞，M1巨噬细胞是对肿瘤细胞的有效防御，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、转移和对化疗的抗性。在临床上，TAM的高肿瘤密度与大多数人和小鼠肿瘤的化疗抗性和更差的临床结果显著相关。TAM的促肿瘤作用已得到很好的表征，但缺乏对TAM如何诱导化疗耐药性的理解。因此，我们建议利用我们实验室开发的一种称为BH3谱的新检测方法来研究TAM如何促进肿瘤促进和化疗耐药性的生物学和机制。 BH 3谱用于确定细胞是否相对接近细胞死亡阈值（相对“引发”死亡），或相对远离阈值（“未引发”）。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。本申请中提出的长期目标集中于激活免疫系统的组分以激活长期抗肿瘤应答。这符合国家癌症研究所的使命，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经存在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。从该项目中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在化疗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，包括可能根除原发性和转移性癌症。

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.