Discovery and Validation of Tumor Immunoevasion Mechanisms

肿瘤免疫逃避机制的发现和验证

• 批准号: 8166119
• 负责人: John R Ohlfest
• 金额: $ 30.74万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-06 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166119
• 关键词: Address; Affect; Animal Model; Animals; Antigens; Biological Assay; Biological Models; Brain Neoplasms; Candidate Disease Gene; Cell Line; Cells; Clinic; Clinical; Clinical Trials; Data; Development; Drug Delivery Systems; Effectiveness; Employee Strikes; Equilibrium; Face; Foundations; Future; Gene Expression; Generations; Genes; Genetic; Genetic Screening; Glioma; Growth; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunologic Memory; Immunologic Monitoring; Immunologic Surveillance; Immunologics; Immunosuppressive Agents; Immunotherapy; Implant; Individual; Infusion procedures; Insertional Mutagenesis; Knowledge; Lead; Leukocytes; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mobile Genetic Elements; Modeling; Morbidity - disease rate; Mus; Mutagenesis; Mutate; Mutation; Oncogene Activation; Oncogenes; Outcome; Ovalbumin; Pathway interactions; Pattern; Pharmaceutical Preparations; Process; Production; Recruitment Activity; Research; Rest; Risk; Role; Site; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Tumor Escape; Tumor Immunity; Tumor Suppressor Proteins; Validation; Work; base; cancer immunotherapy; cancer therapy; design; drug development; functional genomics; gain of function; glioma cell line; human disease; improved; innovation; loss of function; loss of function mutation; macrophage; mortality; mouse model; neoplastic cell; novel; overexpression; pressure; research study; response; tissue culture; tumor; tumorigenesis; vector

DESCRIPTION (provided by applicant): There are currently no comprehensive or satisfactory explanations for how tumors evade the immune response. Much of our knowledge about tumor immunoevasion is limited to individual mechanisms that have been therapeutically targeted with single drugs. However, tumors evolve multiple, redundant strategies to circumvent immune surveillance. This plasticity has contributed to the modest efficacy of cancer immunotherapies that only target one/several pathway(s). The challenge we face is: to comprehensively decipher the mechanisms tumors use to evade immune surveillance. Specifically, how can we determine which of these may be redundant and which may be ideal drug targets (e.g., non-redundant mechanisms)? Similarly, which pathways crucial for tumor immunoevasion might synergize and require several drugs to achieve effective immunotherapy? In order to address this challenge we will establish assays that intentionally select for mutations that allow a tumor to escape an immune response. Using the power of immunologic selective pressure, we will indentify mechanisms that work alone and in combination to allow a tumor to escape immunity. Our central hypothesis is that tumors evolve immunosuppressive gene expression patterns specific to their microenvironment to evade immune attack. We further hypothesize that those changes in gene expression can be rapidly indentified by functional genomics approaches. We have previously used transposon-based mutagenesis to indentify mutations that initiate tumors. Transposons are mobile genetic elements that can be designed to cause mutations that are rapidly identifiable. Herein we will customize transposon-based mutagenesis to identify genes that allow a tumor to thrive despite the presence of high numbers of tumoricidal T cells. Our specific aim is to identify and validate genes that promote escape from immune surveillance in gliomas, an aggressive form of brain cancer. To accomplish this, mutagenic transposons will be mobilized in cultured glioma cells. Mutagenized glioma cells will be implanted into mice with pre-established immunological memory to select for tumor cells that only grow when immune evasion is achieved. In parallel, we will carry out a similar genetic screen in mice with spontaneously arising gliomas that are treated by infusion of tumor-specific T cells. Transposon insertions will be cloned, sequenced and statistically analyzed to identify genes that are repetitively mutated in many tumors that escape immunity. Candidate genes will be functionally validated in tissue culture and animal model experiments to establish cause and affect relationships between their expression and immunoevasion. IMPACT: The identification of integrated pathways that tumors require to escape immune responses in order to thrive, which will ultimately lead to the development of drugs that increase the efficacy of cancer immunotherapy. PUBLIC HEALTH RELEVANCE: Tumors are continuously eliminated in our bodies by a process called "immunosurveillance". When immunosurveillance fails, clinically apparent tumors arise that cause significant morbidity and mortality. Therefore, discovery of the processes that allow a tumor to escape the immune response is vital to improve the effectiveness of immune-based treatments for cancer. Herein we will establish assays that allow for the rapid identification of novel mechanisms by which tumors escape the immune response. Several of these "immune escape" mechanisms will be validated as potential targets for future drug development. The ultimate impact of these studies will be the development of more effective immune-based therapies for the treatment of cancer.

描述(申请人提供)：目前还没有关于肿瘤如何逃避免疫反应的全面或令人满意的解释。我们对肿瘤免疫逃逸的大部分知识仅限于单一药物治疗靶点的个别机制。然而，肿瘤进化出多种多余的策略来规避免疫监视。这种可塑性导致了仅针对一种/几种途径的癌症免疫疗法的适度疗效(S)。我们面临的挑战是：全面破译肿瘤用来逃避免疫监视的机制。具体地说，我们如何确定这些机制中哪些可能是冗余的，哪些可能是理想的药物靶点(例如，非冗余机制)？同样，哪些对肿瘤免疫逃避至关重要的途径可能会协同作用，并需要几种药物才能实现有效的免疫治疗？为了应对这一挑战，我们将建立有意选择允许肿瘤逃脱免疫反应的突变的检测方法。利用免疫选择压力的力量，我们将确定单独和联合作用的机制，使肿瘤逃脱免疫。我们的中心假设是，肿瘤进化出特定于其微环境的免疫抑制基因表达模式，以逃避免疫攻击。我们进一步假设，这些基因表达的变化可以通过功能基因组学方法快速识别。我们以前曾使用基于转座子的突变来鉴定引发肿瘤的突变。转座子是一种可移动的遗传元件，可以被设计成导致快速识别的突变。在这里，我们将定制基于转座子的突变，以识别允许肿瘤在存在大量杀瘤T细胞的情况下仍能生长的基因。我们的具体目标是识别和验证促进胶质瘤逃避免疫监视的基因，胶质瘤是一种侵袭性的脑癌。为了实现这一点，将在培养的胶质瘤细胞中动员诱变转座子。突变的胶质瘤细胞将被植入具有预先建立的免疫记忆的小鼠体内，以选择只有在实现免疫逃避时才会生长的肿瘤细胞。同时，我们将在自发性胶质瘤小鼠中进行类似的基因筛查，这些小鼠接受肿瘤特异性T细胞的治疗。将对转座子插入进行克隆、测序和统计分析，以确定在许多逃脱免疫的肿瘤中重复突变的基因。候选基因将在组织培养和动物模型实验中进行功能验证，以确定它们的表达和免疫逃避之间的因果关系。影响：确定肿瘤为了茁壮成长而需要逃避免疫反应的综合途径，这最终将导致提高癌症免疫治疗效果的药物的开发。 与公共卫生相关：我们体内的肿瘤通过一种称为“免疫监测”的过程被持续清除。当免疫监测失败时，临床上明显的肿瘤就会出现，导致显著的发病率和死亡率。因此，发现使肿瘤逃脱免疫反应的过程对于提高基于免疫的癌症治疗的有效性至关重要。在这里，我们将建立允许快速识别肿瘤逃避免疫反应的新机制的检测方法。这些“免疫逃逸”机制中的几种将被证实为未来药物开发的潜在靶点。这些研究的最终影响将是开发更有效的基于免疫的癌症治疗方法。