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 释放免疫系统对抗患者肿瘤的进展已经改变了临床前景 最近被认为无法治疗的晚期癌症，如黑色素瘤、膀胱癌和非 小细胞肺癌。然而，为了使免疫检查点治疗有效，必须有一个预 免疫细胞现有的识别癌症的能力，与肿瘤本身有关，其中高 基因突变负担导致抗原肽被认为是外来的。实际上，免疫 检查点阻断抗癌疗法利用并释放预先存在的炎症信号 对抗肿瘤的新抗原。实现长期持久治疗和扩大治疗范围的障碍 然而，观察到的反应目前很大程度上未知。尽管如此，直觉上认为低 新抗原负荷或其总体表达减少会削弱治疗反应，并可能 因此也能够促进治疗进展。为此，我们着手定义肿瘤固有的 影响癌症免疫原性并可能调节免疫效应的分子级联 检查点治疗。在初步研究中，我们发现转录线索参与细胞命运 已经进化到规避免疫的肿瘤的决定和分化减少 认出。肿瘤抗原对于免疫监视至关重要，因此可以提高其免疫功能 通过增加谱系特异性转录回路的内在水平可能会促进随后的肿瘤 承认和毁灭。在两个具体目标中，我们将 a) 确定谱系特异性转录如何 调节与代谢线索相协调，以改变与相关的转录库 抗原性降低； b) 提供提高肿瘤抗原性的概念验证，以增强 免疫检查点阻断反应。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并推动进展。此外，我们的 工作还可以提供可用于治疗开发的关键途径知识。