Exploring mechanisms to increase cancer cell antigenicity by modulating lineage-specific transcription in tumors

探索通过调节肿瘤中谱系特异性转录来增加癌细胞抗原性的机制

• 批准号: 9378541
• 负责人: Hans Ragnar WIDLUND
• 金额: $ 7.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378541
• 关键词: Affect; Alleles; CD8-Positive T-Lymphocytes; Cell Line; Cell Shape; Cells; Clinical; Critical Pathways; Cues; DNA Sequence Alteration; Data; Differentiated Gene; Disease; Disease Management; Down-Regulation; Effectiveness; Employee Strikes; Event; Frequencies; Genes; Genetic Transcription; Goals; Growth; Health; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Surveillance; Infiltration; Inflammation; Inflammatory; Intuition; Investigation; Knowledge; Ligands; Link; Malignant Neoplasms; Measurable; Mediating; Melanoma Cell; Metabolic; Metabolism; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Outcome; PDCD1LG1 gene; Pathway interactions; Patients; Peptides; Phenotype; Signal Transduction; T-Lymphocyte; Therapeutic Uses; Transcript; Transcriptional Regulation; Treatment Effectiveness; Tumor Antigens; Work; anti-cancer therapeutic; base; bladder Carcinoma; cancer cell; cancer therapy; checkpoint therapy; experience; experimental study; falls; genome-wide; immune checkpoint; immunogenicity; improved; improved outcome; in vivo; inducible gene expression; melanocyte; melanoma; mutant; optimism; outcome forecast; prevent; receptor; response; treatment response; tumor; tumor growth; tumor microenvironment

SUMMARY Advances in unleashing the immune system against patients' tumors has altered the clinical landscape for recently thought untreatable advanced stage cancers, such as melanoma, bladder carcinoma, and non- small cell lung cancer. For immune checkpoint treatment to be effective, however, there must be a pre- existing ability for immune cells to recognize the cancer, which relates to the tumor itself and wherein a high genetic mutation burden result in antigenic peptides that are recognized as foreign. In effect, immune checkpoint blocking anti-cancer therapeutics exploit and release pre-existing inflammatory signals directed against the tumors' neoantigens. The barriers to achieving long-term durable treatment and broadening the observed responses are however currently largely unknown. Nevertheless, it is intuitive that a low neoantigen burden, or their reduced overall expression, blunt the therapeutic responses and may consequently also enable treatment progression. To this end, we have set out to define tumor inherent molecular cascades that impact a cancer's immunogenicity and that may modulate effects of immune checkpoint treatment. In preliminary studies we have found that transcriptional cues involved in cell-fate determination and differentiation are reduced in tumors that have evolved to circumvent immune recognition. Guided by the fact that tumor-antigens are critical to immune-surveillance, elevating their inherent levels by increasing lineage-specific transcriptional circuits may promote consequent tumor recognition and destruction. In two specific aims, we will a) determine how lineage-specific transcriptional regulation is coordinated with metabolic cues to alter a transcriptional repertoire that is associated with reduced antigenicity; and b) provide proof-of-concept for elevating antigenicity of tumors to enhance immune checkpoint blockage responses. Successful completion of the proposed studies may improve our understanding of how tumors co-evolve to evade immune recognition and drive progression. In addition, our work may also provide critical pathway knowledge that could be used for therapeutic exploit.

概括 释放针对患者肿瘤的免疫系统的进步改变了临床局势 最近认为，不可治疗的晚期癌症，例如黑色素瘤，膀胱癌和非 - 小细胞肺癌。但是，要使免疫检查点的治疗有效，必须有一个前 现有的免疫细胞识别癌症的能力，与肿瘤本身有关 遗传突变负担会导致被识别为异物的抗原肽。实际上，免疫 检查点阻止抗癌治疗药开发并释放定向的炎症信号 针对肿瘤的新抗原。实现长期耐用处理并扩大的障碍 但是，观察到的响应目前在很大程度上未知。然而，直观的是 Neoantigen负担或其总体表达减少，钝化治疗反应，可能 因此，还可以实现治疗进展。为此，我们已经着手定义固有的肿瘤 影响癌症的免疫原性的分子级联反应并可能调节免疫的影响 检查点处理。在初步研究中，我们发现涉及细胞命令的转录提示 在已经演变为避免免疫的肿瘤中，测定和分化减少了 认出。在肿瘤抗原对免疫疗法至关重要的事实的指导下，提升了它们 固有水平通过增加谱系特异性转录电路可能会促进肿瘤 认可和破坏。在两个具体目标中，我们将a）确定谱系特定转录的方式 调节与代谢线索协调，以改变与之相关的转录曲目 抗原性降低； b）提供概念证明，以提高肿瘤的抗原性以增强 免疫检查点阻滞响应。成功完成拟议的研究可能会改善我们的 了解肿瘤如何共同进化以逃避免疫识别和驱动进展。另外，我们的 工作还可以提供可用于治疗性利用的关键途径知识。