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：
10350566
负责人：
Hans Ragnar WIDLUND
金额：
$ 34.12万
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350566
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 Frequencies Future Genetic Genetic Transcription Goals Growth Health Human Immune Immune Evasion Immune checkpoint inhibitor Immune mediated destruction Immune response Immunity Immunologic Surveillance Immunology Immunosuppression Immunotherapeutic agent Investigation Knowledge Ligands Link MEKs Malignant Neoplasms Measurement Mediating Melanoma Cell Metabolic Metabolism Mitochondria Modeling Molecular Mus Mutation Myeloid-derived suppressor cells Oncogenes Oncogenic Outcome Patients Peptides Phenotype Physicians Process Prognosis Proteins Regulation Regulatory T-Lymphocyte Research Personnel Research Proposals Role Shapes Signal Transduction Specimen T-Lymphocyte T-Lymphocyte Subsets Therapeutic Therapeutic Effect Transcriptional Regulation Treatment outcome Tumor Escape Up-Regulation Work YY1 Transcription Factor advanced disease anti-PD1 therapy base checkpoint therapy combinatorial experience immune checkpoint immune checkpoint blockade immune clearance immunogenic immunogenicity immunoregulation improved improved outcome in vivo indexing individual patient inhibitor innovation melanocyte melanoma mutant neoantigens neoplastic cell prevent programmed cell death protein 1 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靶向癌基因的化学抑制剂具有彻底改变了癌症的治疗景观，现在为患者提供了真正的希望疾病。但是，尽管有些患者会受益，但其他患者根本不会做出回应 - 困境这与肿瘤的遗传组成密切相关。鉴定分子过程这使得迫切需要对这种疗法的积极反应，这迫切需要，并且可能需要确定可以改善结果的理性组合方法。免疫检查点抑制剂疗法，有证据积累，表明患者癌症的突变烧伤，新抗原辣椒的频率增加会引起免疫原性。为了生长，这种抗原肿瘤必须开发机制，使其能够逃避免疫介导的破坏，这使得这些肿瘤容易受到逆转肿瘤免疫进化的免疫检查点疗法的影响。来自我们的正在进行的有关黑色素瘤细胞如何洗脱癌细胞靶向疗法的效率的研究，我们已经拥有鉴定出一种免疫抑制分子，其表达水平直接连接到肿瘤代谢状态。而以癌基因为靶向疗法倾向于引起黑色素瘤的表达增加抗原是由代谢需求改变和MITF介导的线粒体调节引起的通过PGC1的生物发生，该免疫抑制分子的水平急剧下降。因此，这些数据表明，增加的免疫监测可能与目标的影响相交疗法。我们的初步研究表明，致癌信号控制转录调控该免疫抑制分子的转录调节，并且对其水平的操纵改变了体内肿瘤生长与肿瘤免疫原性的变化有关。此外，我们证明了该分子表达的升高与否则将是的患者的预后不良相关预计将从免疫检查点疗法中受益。在此提案中，我们将进行剖析的研究控制该免疫抑制分子表达水平的分子机制。我们将进一步评估该蛋白质修饰免疫检查点疗法的影响的程度，并确定是否可以使用其前瞻性使用来告知临床决策。成功完成拟议的研究应改善临床管理和提案组合的投资目标。