Targeting M2-Tumor Associated Macrophages to overcome tumor immunity in metastatic castration-resistant prostate cancer

前列腺癌（PCa）一旦转移是致命的，并且在美国仍然是一个未满足的医疗需求。 美国的越来越多的证据表明，前列腺肿瘤微环境， 包围癌细胞，显著促进其进展，规避当前疗法， 对新的免疫检查点疗法的抗性及其存活率。使用临床样本，主要 研究人员发现，转移性去势抵抗性前列腺癌的肿瘤微环境 （mCRPC）输注富含M2巨噬细胞的反应性基质，称为M2-肿瘤相关 巨噬细胞（M2-TAMs）。他以前的研究部分阐明了M2-TAMs和反应性基质是如何在细胞内形成的。 与原发性和转移性疾病相关，在M2-TAM上鉴定了五种新的表面富集标志物， 已经帮助证明M2-TAMs是PCa上皮向间质转化（EMT）的关键调节因子 和肿瘤发生。因此，需要设计靶向肿瘤内M2-TAM的靶向疗法， 微环境是非常必要的。其他研究已经证明了M2-TAM在 血管生成、转移及其对谷氨酰胺代谢的依赖性。根据他的数据和其他 主要研究者假设M2-TAM是mCRPC的理想治疗靶点， 使mCRPC对免疫疗法产生耐药性。该建议将确定新的M2-TAM标记物在大肠杆菌中的表达。 mCRPC（特定目的1），并评估前列腺癌中M2-TAM的消除是否可以逆转mCRPC 免疫治疗抗性（特异性目的2，3）。这将是第一个使用同基因mCRPC肿瘤的工作机构 用抗CD 206肽（RP 182）或新型谷氨酰胺拮抗剂JHU 083治疗的模型， 免疫治疗和肿瘤微环境的全面免疫学分析。校长 研究人员还将学习完成该计划下拟议研究所需的新技术 团队（Drs. Drake，McConkey，Pardoll，Pienta，and Powell）和他的病理学家顾问（Dr. De Marzo）， 他们在PCa生物学、mCRPC治疗、癌症代谢、单细胞RNA 测序和癌症免疫疗法。重要的是，他的咨询委员会集体拥有非常强大的轨道， 培训临床和博士后研究员的记录，他们已经成功地过渡到 顶级研究机构的独立调查员。他还将参与并出席国家 研讨会，参加实验室生物统计学，癌症代谢和免疫代谢，单细胞 RNA测序，Jr.教师领导计划，赠款写作研讨会，并在运行一个实验室的培训。 将K22奖励期间学到的这些新技能与他之前在癌症生物学方面的培训相结合， 癌症免疫学，将确保强大的技术基础，推出一个独立的实验室解剖 和针对先天免疫细胞及其机制负责免疫治疗抗性， 这在mCRPC中定义非常差。

Prostate cancer (PCa) is deadly once it metastasizes and continues to be an unmet medical need here in the United States. Increasing evidence has demonstrated that the prostate tumor microenvironment which, surrounds the cancer cells, significantly contributes to its progression, circumvention of current therapies, resistance to newer immune checkpoint therapies, and its survival. Using clinical samples, the principal investigator has found that the tumor microenvironment of metastatic castration-resistant prostate cancer (mCRPC) is infused with reactive stroma enriched with M2 macrophages known as M2-tumor-associated macrophages (M2-TAMs). His previous studies have partly elucidated how M2-TAMs and reactive stroma associate with primary and metastatic disease, identified five new surface-enriched markers on M2-TAMs, and has helped demonstrate that M2-TAMs are key regulators of PCa epithelial-to-mesenchymal transition (EMT) and tumorigenesis. Therefore, the need to design targeted therapies that target M2-TAMs within the tumor microenvironment is sorely needed. Other studies have demonstrated the importance of M2-TAMs in angiogenesis, metastasis, and their dependence on glutamine metabolism. Based on his data and that of other groups, the principal investigator hypothesizes that M2-TAMs are ideal therapeutic targets in mCRPC and help confer mCRPC resistant to immunotherapy. This proposal will determine novel M2-TAM marker expression in mCRPC (Specific Aim 1) and assess if the elimination of M2-TAMs in prostate cancer can reverse mCRPC immunotherapy resistance (Specific Aims 2, 3). This will be the first body of work using syngeneic mCRPC tumor models treated with either anti-CD206 peptide (RP182) or a novel glutamine antagonist, JHU083 followed by immunotherapy and a comprehensive immunological analysis of the tumor microenvironment. The principal investigator will also learn new techniques necessary to accomplish the proposed research under the advisement team (Drs. Drake, McConkey, Pardoll, Pienta, and Powell) and his pathologist consultant (Dr. De Marzo) all of whom have pioneering expertise in PCa biology, mCRPC treatment, cancer metabolism, single-cell RNA sequencing, and cancer immunotherapy. Importantly, his advisory committee collectively has a very strong track record of training both clinical and postdoctoral fellows who have been successful in transitioning into independent investigators at top tier research institutions. He will also engage in and present at national seminars, take coursework on laboratory biostatistics, cancer metabolism and immuno-metabolism, single cell RNA-sequencing, Jr. Faculty leadership program, grant-writing seminars, and training on running a laboratory. Combining these new skills learned during the K22 award period with his prior training in cancer biology and cancer immunology, will ensure a strong technical foundation to launch an independent laboratory dissecting and targeting innate immune cells and their mechanisms responsible for immunotherapy resistance, both of which are very poorly defined in mCRPC.