Tumor microenvironment: Impact on T cell tumor-targeting, activation and survival

肿瘤微环境：对 T 细胞肿瘤靶向、激活和存活的影响

• 批准号: 8297452
• 负责人: Ronald George Blasberg
• 金额: $ 52.07万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-09 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297452
• 关键词: Acidosis; Affect; Animal Model; Animals; Antigen Receptors; Biological Assay; Blood flow; Bone neoplasms; Cancer Patient; Cell Therapy; Cell physiology; Cells; Characteristics; Clinic; Clinical Research; Data; Drug Design; Glutamate Carboxypeptidase II; Human; Hypoxia; Image; Imaging Techniques; Immune response; Immune system; Immunocompetent; Immunotherapy; Interdisciplinary Study; Intervention; Lung Neoplasms; Magnetic Resonance Spectroscopy; Malignant neoplasm of prostate; Measurement; Measures; Mediating; Metastatic Lesion; Modality; Modeling; Monitor; Patients; Positron-Emission Tomography; Production; Prostate; Records; Reporter; Reporter Genes; Research; Research Infrastructure; Signal Transduction; Stromal Neoplasm; System; T cell therapy; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Transforming Growth Factors; Translating; Tumor-Derived; cancer stem cell; carbonate dehydratase; cytokine; cytotoxicity; experience; extracellular; improved; inhibitor/antagonist; lactate dehydrogenase A; multimodality; novel; response; stem cell therapy; trafficking; treatment strategy; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): An abnormal tumor microenvironment can impair T cell function and limit the immune response. Tumor- derived lactate and an acidic microenvironment, as well as tumor/stromal secretion of TGF¿ can independently and synergistically suppress T cell proliferation, cytokine production and cytotoxicity. We propose to alter components of the tumor microenvironment (pHe, lactate and TGF¿) and assess these effects on PSMA chimeric antigen receptor (CAR) specific T cell therapy in two highly aggressive, immunocompetent animal models of prostate cancer with orthotopic, lung and bone tumor growth. Our central theme and hypothesis is that a markedly abnormal tumor microenvironment affects T cell tumor-targeting and survival, as well as T cell activation, proliferation and effector-function, and that these T cell functions can be monitored using novel dual reporter systems. A constitutive-reporter will be used for imaging T cell trafficking, tumor targeting and survival, and inducible-reporter systems will concurrently image and assess T cell function. One inducible reporter will monitor T cell activation mediated through a PSMA- specific CAR; the other will monitor TGF¿-signaling in T cells. The effects of genetically induced abnormalities in the tumor microenvironment (low pHe, high lactate and high TGF¿) on T cell trafficking and function will be assessed using multimodality imaging techniques. The status of the tumor microenvironment will be assessed repeatedly in the same animal using MRIS to measure pHe and lactate, and microPET to assess tumor hypoxia during tumor growth and during adoptive T cell therapy. Additional ex vivo immunohistochemical cell assays will independently assess the tumor microenvironment and confirm T cell status. We also expect that "normalization" of different components of the tumor microenvironment (pHe, lactate and TGF¿) using pharmacological intervention will significantly enhance T cell therapy; therefore, we have included therapeutic sub-aims to test this hypothesis. The relevance and impact of these studies are that: 1) Lactate, pHe, and TGF¿ levels in the tumor microenvironment are frequently abnormal, particularly in more aggressive tumors, and are associated with a reduced immune response. 2) Importantly, there exist specific treatment modalities to "normalize" these components, and they will be investigated. 3) Many of the imaging strategies developed and used in this project (e.g., MRSI to measure pHe and lactate) could be translated to clinical studies, where monitoring T cell trafficking and function can be monitored in patients using human reporter genes and PET imaging, and where adoptive T cell treatment strategies could be more fully evaluated. PUBLIC HEALTH RELEVANCE: An abnormal microenvironment is characteristic of aggressive prostate cancer, and is associated with a reduced immune response to the tumor; therefore, we propose to study the effects of specific abnormalities in the tumor microenvironment on the immune system. We expect that "normalizing" these abnormalities in the tumor microenvironment will significantly improve the therapeutic response to immunotherapy. The imaging strategies and therapeutic counter-measures developed in this proposal could be applied to patients with prostate cancer, and could serve as a model for similar studies in other cancers and for stem cell therapy as well.

描述(申请人提供)：异常的肿瘤微环境会损害T细胞功能，限制免疫反应。肿瘤来源的乳酸和酸性微环境以及肿瘤/间质分泌的转化生长因子？可以独立和协同地抑制T细胞的增殖、细胞因子的产生和细胞毒作用。我们建议改变肿瘤微环境的成分(苯丙氨酸、乳酸和转化生长因子)，并在两种高侵袭性、免疫活性的前列腺癌原位、肺和骨肿瘤生长的动物模型中评估这些因素对PSMA嵌合抗原受体(CAR)特异性T细胞治疗的影响。我们的中心主题和假设是，显著异常的肿瘤微环境影响T细胞的肿瘤靶向和生存，以及T细胞的激活、增殖和效应功能，并且这些T细胞的功能可以通过新的双重报告系统进行监测。构成报告将用于成像T细胞运输、肿瘤靶向和生存，可诱导报告系统将同时成像和评估T细胞功能。一个可诱导的报告将监测通过PSMA特异性CAR介导的T细胞激活；另一个将监测T细胞中的转化生长因子信号。基因诱导的肿瘤微环境异常(低Phe、高乳酸和高转化生长因子)对T细胞运输和功能的影响将使用多模式成像技术进行评估。在同一动物中，肿瘤微环境的状态将被重复评估，使用MRIS测量Phe和乳酸，并使用microPET评估肿瘤生长期间和过继T细胞治疗期间的肿瘤缺氧。额外的体外免疫组织化学细胞分析将独立评估肿瘤微环境并确认T细胞状态。我们还预计，使用药物干预使肿瘤微环境的不同成分(苯丙氨酸、乳酸和转化生长因子)“正常化”将显著增强T细胞治疗；因此，我们纳入了治疗子目标来检验这一假说。这些研究的相关性和影响是：1)肿瘤微环境中的乳酸、苯丙氨酸和转化生长因子水平经常异常，特别是在更具侵袭性的肿瘤中，并与免疫反应降低有关。2)重要的是，有具体的治疗方式可以使这些成分“正常化”，并将对其进行调查。3)该项目中开发和使用的许多成像策略(例如，用于测量Phe和乳酸的MRSI)可以转化为临床研究，可以使用人类报告基因和PET成像来监测患者的T细胞运输和功能，并且可以更全面地评估采用的T细胞治疗策略。 公共卫生相关性：侵袭性前列腺癌的特征是微环境异常，并与对肿瘤的免疫反应降低有关；因此，我们建议研究肿瘤微环境中特定异常对免疫系统的影响。我们期望将肿瘤微环境中的这些异常“正常化”将显著改善免疫治疗的治疗反应。该建议中提出的成像策略和治疗对策可应用于前列腺癌患者，并可作为其他癌症的类似研究和干细胞治疗的典范。