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

靶向 M2 肿瘤相关巨噬细胞克服转移性去势抵抗性前列腺癌的肿瘤免疫

• 批准号: 10207549
• 负责人: Jelani Chinelo Zarif
• 金额: $ 15.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207549
• 关键词: Advisory Committees; Autopsy; Biometry; Cancer Biology; Cancer Cell Growth; Cancer Patient; Career Transition Award; Castration; Cell Proliferation; Cells; Cessation of life; Clinical; Coculture Techniques; Cytotoxic T-Lymphocytes; Data; Dependence; Disease; Effectiveness; Ensure; Environment; Etiology; Faculty; Foundations; Glutamine; Goals; Grant; Growth; Growth Factor; Health; Human; Immune; Immune response; Immune system; Immunocompetent; Immunologics; Immunotherapy; In Vitro; Infiltration; Institution; K22 Award; Knowledge; Laboratories; Lead; Leadership; Learning; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Membrane Glycoproteins; Metabolism; Mission; Modeling; Morbidity - disease rate; Neoplasm Metastasis; PC3 cell line; Pathologist; Peptides; Postdoctoral Fellow; Pre-Clinical Model; Principal Investigator; Prognosis; Prognostic Marker; Prostate Cancer therapy; Prostatic Neoplasms; Public Health; Research; Research Personnel; Research Proposals; Resected; Resistance; Role; Running; Sampling; Solid Neoplasm; Surface; T-Cell Activation; Techniques; Testing; Tissues; Training; Tumor Immunity; Tumor-associated macrophages; Tumor-infiltrating immune cells; United States; Work; Writing; angiogenesis; anti-CTLA4; anti-PD-1; anti-tumor immune response; base; cancer cell; cancer diagnosis; cancer immunotherapy; cancer therapy; castration resistant prostate cancer; checkpoint therapy; clinically relevant; cytokine; design; effective therapy; epithelial to mesenchymal transition; fighting; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; macrophage; mannose receptor; men; mouse model; neoplastic cell; novel; prevent; programs; prostate cancer cell; prostate cancer cell line; prostate cancer model; refractory cancer; response; single-cell RNA sequencing; skills; targeted treatment; therapeutic target; tumor; tumor growth; tumor immunology; tumor metabolism; tumor microenvironment; tumor-immune system interactions; tumorigenesis; wound healing

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.

前列腺癌（PCA）是致命的，一旦转移了，并且在这里仍然是未满足的医疗需求 美国。越来越多的证据表明，前列腺肿瘤微环境，这是 围绕癌细胞，显着有助于其进展，当前疗法的规避， 对新的免疫检查点疗法及其生存的抗性。使用临床样本，校长 研究人员发现，转移性cast割前列腺癌的肿瘤微环境 （MCRPC）注入了充满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-TAM和反应性基质 与原发性和转移性疾病结合，在M2-TAM上鉴定出五个新的表面富含标记，并确定 已经帮助证明了M2-TAM是PCA上皮到间质转变（EMT）的关键调节剂 和肿瘤发生。因此，需要设计靶向M2-TAM在肿瘤内的靶向疗法 非常需要微环境。其他研究表明，M2-TAM在 血管生成，转移及其对谷氨酰胺代谢的依赖。根据他的数据和其他数据 小组，主要研究人员假设M2-TAM是MCRPC中理想的治疗靶标的，并有助于 赋予MCRPC对免疫疗法的抗性。该建议将确定新颖的M2-TAM标记表达 MCRPC（特定目标1）并评估消除前列腺癌中M2-TAM是否可以逆转MCRPC 免疫疗法抗性（特定目标2、3）。这将是使用Syngeneic MCRPC肿瘤的第一个工作 用抗CD206肽（RP182）或新型谷氨酰胺拮抗剂处理的模型，JHU083，然后是 免疫疗法和肿瘤微环境的全面免疫学分析。校长 调查人员还将学习根据咨询完成拟议研究所需的新技术 团队（Drake，McConkey，Pardoll，Pienta和Powell博士）和他的病理学家顾问（De Marzo博士） 在PCA生物学，MCRPC治疗，癌症代谢，单细胞RNA方面具有开创性的专业知识 测序和癌症免疫疗法。重要的是，他的咨询委员会统称很强 临床和博士后研究员的培训记录，他们成功过渡到 顶级研究机构的独立研究人员。他还将参与国家 研讨会，参加实验室生物统计学，癌症代谢和免疫代谢的课程，单细胞 RNA-Serviceing，小教师领导力计划，授予写作研讨会以及经营实验室的培训。 将这些在K22奖项期间学到的新技能与他先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，以启动独立的实验室解剖 并针对先天免疫细胞及其负责免疫疗法抗性的机制 在MCRPC中定义很差。