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

前列腺癌(PCA)一旦转移就是致命的，在这里仍然是一个未得到满足的医疗需求 美国。越来越多的证据表明，前列腺癌的微环境， 包围着癌细胞，极大地促进了癌细胞的发展，绕过了目前的治疗方法， 对新的免疫检查点疗法的抵抗力及其存活率。使用临床样本，校长 研究人员发现，转移性去势抵抗前列腺癌的肿瘤微环境 (MCRPC)注入活性间质，富含M2巨噬细胞，称为M2肿瘤相关细胞 巨噬细胞(M2-TAMs)。他之前的研究部分阐明了M2-TAMs和反应性间质是如何 与原发和转移性疾病相关，确定了M2-TAMs上五个新的表面富集型标记物，以及 已经证明M2-TAMs是Pca上皮向间充质转化(EMT)的关键调节因子 和肿瘤的发生。因此，需要设计针对肿瘤内M2-TAMs的靶向治疗 微环境是迫切需要的。其他研究已经证明了M2-TAMs在 血管生成、转移及其对谷氨酰胺代谢的依赖。根据他和其他人的数据 主要研究人员假设M2-TAMs是mCRPC和HELP的理想治疗靶点 授予mCRPC对免疫治疗的抵抗力。这一提议将决定新的M2-标记在 MCRPC(特异性目标1)，并评估前列腺癌M2-TAMs的消除是否可以逆转mCRPC 免疫治疗耐药(特异性目标2、3)。这将是第一个使用同基因mCRPC肿瘤的工作 用抗CD206多肽(RP182)或新型谷氨酰胺拮抗剂JHU083处理动物模型 免疫治疗和肿瘤微环境的全面免疫学分析。校长 调查员还将学习必要的新技术，以完成建议中的研究 团队(德雷克、麦康基、帕多尔、皮恩塔和鲍威尔)和他的病理学家顾问(德马佐博士) 他们在前列腺癌生物学、mCRPC治疗、癌症代谢、单细胞RNA等领域拥有开创性的专业知识 测序和癌症免疫治疗。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成功过渡到 顶级研究机构的独立调查人员。他还将参与并在National 研讨会，选修实验室生物统计学、癌症代谢和免疫代谢、单细胞 RNA测序，Jr.教师领导力计划，拨款撰写研讨会，以及实验室运营培训。 将在K22颁奖期间学到的这些新技能与他以前接受的癌症生物学和 癌症免疫学，将确保强大的技术基础，推出独立的实验室解剖 和靶向先天免疫细胞及其导致免疫治疗耐药性的机制，两者都 它们在mCRPC中定义得很差。

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.