Coordinating tumor differentiation and immune suppression with the metabolic state and treatment outcome

协调肿瘤分化和免疫抑制与代谢状态和治疗结果

基本信息

批准号：
9259429
负责人：
Hans Ragnar WIDLUND
金额：
$ 41.13万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-17 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9259429
关键词：
Affect Antigens BRAF gene Biogenesis Biological Markers Biology Blocking Antibodies CCAAT-Enhancer-Binding Proteins CD 200 CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cells Charge Chemicals Clinic Clinical Clinical Management Clinical Treatment Clinical effectiveness Cues Data Disease remission Employee Strikes Frequencies Future Genetic Genetic Transcription Goals Growth Health Human Immune Immune Evasion Immune checkpoint inhibitor Immune response Immunity Immunologic Surveillance Immunology Immunosuppression Immunosuppressive Agents Investigation Knowledge Ligands Link Malignant Neoplasms Measurement Mediating Melanoma Cell Metabolic Metabolism Mitochondria Modeling Molecular Mus Mutation Myelogenous Oncogenes Oncogenic Outcome Patients Peptides Phenotype Physicians Process Proteins Regulation Regulatory T-Lymphocyte Research Personnel Research Proposals Role Shapes Signal Transduction Specimen Suppressor-Effector T-Lymphocytes T-Lymphocyte T-Lymphocyte Subsets Therapeutic Therapeutic Effect Transcriptional Regulation Treatment outcome Up-Regulation Work advanced disease base checkpoint therapy combinatorial experience immune checkpoint immune checkpoint blockade immune clearance immunogenic immunogenicity immunoregulation improved improved outcome in vivo indexing individual patient inhibitor/antagonist innovation killings melanocyte melanoma mutant neoplastic cell outcome forecast prevent prospective receptor response success targeted treatment treatment response trend tumor tumor growth tumor microenvironment

项目摘要

SUMMARY Therapeutic immune checkpoint blocking antibodies and oncogene-targeted chemical inhibitors have revolutionized the treatment landscape for cancers, and now provide real hope to patients with advanced disease. However, while some patients will experience benefit, others will not respond at all – a dilemma that is intimately linked to the genetic composition of the tumors. Identification of the molecular processes that enable, as well as preclude, positive responses to such therapies are urgently needed, and are likely to identify rational combinatorial approaches that will improve outcome. For immune checkpoint inhibitor therapies, evidence has accumulated to suggest that the mutational burden in the patients' cancer, through an increased frequency of neoantigen peptides, causes immunogenicity. In order to grow, such antigenic tumors must develop mechanisms that enable them to evade immune-mediated destruction, which makes these tumors vulnerable to immune checkpoint therapies that reverses tumor immune evasion. From our ongoing studies on how melanoma cells elude the efficacy of oncogene-targeted therapies, we have identified an immunosuppressive molecule whose expression levels are directly linked to the tumors metabolic state. While oncogene-targeted therapies tend to cause an increased expression of melanoma antigens, which is triggered by altered metabolic demands and MITF-mediated regulation of mitochondrial biogenesis through PGC1there is a drastic decrease in the levels of this immune suppressive molecule. Hence, these data suggested that increased immune surveillance may intersect with the effects of targeted therapies. Our preliminary studies demonstrate that oncogenic signaling governs transcriptional regulation of transcriptional regulation of this immune suppressive molecule, and that manipulation of its levels alters tumor growth in vivo, associated with changes in tumor immunogenicity. Furthermore, we demonstrate that heightened expression of this molecule is correlated with poor prognosis in patients who otherwise would be expected to benefit from immune checkpoint therapies. In this proposal, we will perform studies that dissect the molecular mechanisms that control this immune suppressive molecule's expression levels. We will further assess the degree to which this protein modifies the effects of immune checkpoint therapies, and determine if its prospective use might be used to inform clinical decisions. Successful completion of the proposed studies should improve clinical management and propose combinatorial targets for investigation.

概括治疗性免疫检查点阻断抗体和针对癌基因的化学抑制剂已彻底改变了癌症的治疗格局，现在为晚期患者带来了真正的希望然而，虽然有些患者会受益，但其他患者则根本没有反应——这是一个两难的境地。这与肿瘤的分子过程的遗传组成密切相关。迫切需要使这些疗法产生积极反应，并阻止这种疗法的积极反应，并且很可能确定可改善免疫检查点抑制剂结果的合理组合方法。治疗中，积累的证据表明，患者癌症中的突变负担，通过新抗原肽的频率增加，导致免疫原性增长，这样的抗原。肿瘤必须发展出使它们能够逃避免疫介导的破坏的机制，这使得这些肿瘤容易受到免疫检查点疗法的影响，从而逆转肿瘤的免疫逃避。关于黑色素瘤细胞如何逃避癌基因靶向疗法的功效的持续研究，我们有鉴定出一种免疫抑制分子，其表达水平与肿瘤直接相关而癌基因靶向治疗往往会导致黑色素瘤表达增加。抗原，这是由代谢需求改变和 MITF 介导的线粒体调节触发的通过PGC1的生物发生，这种免疫抑制分子的水平急剧下降。因此，这些数据表明，增强的免疫监视可能与靶向药物的效果相交叉。我们的初步研究表明致癌信号控制转录调控。这种免疫抑制分子的转录调节，并且对其水平的操纵会改变体内肿瘤生长与肿瘤免疫原性的变化相关。此外，我们证明了这一点。该分子的完全表达与患者的不良预后相关，否则这些患者的预后会很差。预计将从免疫检查点疗法中受益在本提案中，我们将进行剖析研究。我们将了解控制这种免疫抑制分子表达水平的分子机制。进一步评估该蛋白质改变免疫检查点疗法效果的程度，以及确定其预期用途是否可用于指导临床决策的成功完成。拟议的研究应改善临床管理并提出研究的组合目标。