Harnessing the repetitive genome for cancer immunotherapy

项目摘要 这份科斯提案描述了一个为期五年的癌症表观遗传学和肿瘤免疫学职业发展培训计划。Gabriel Griffin博士已在Brigham and Women's Hospital和哈佛医学院（HMS）完成了血液病理学的临床培训，并将开始这项研究计划，目标是为独立的实验室职业培训，研究癌症免疫调节的基本机制。在这个培训计划中，格里芬博士将进一步发展转座因子和肿瘤免疫研究的专业知识。并获得基因组拓扑学领域的新技能。包括增强子-启动子环的功能分析，这将使他未来的研究成为可能。他的导师布拉德利伯恩斯坦博士（丹娜-法伯癌症研究所癌症生物学主席，HMS病理学教授，麻省理工学院和哈佛布罗德研究所表观基因组学项目主任）是癌症表观基因组学领域的国际领导者，在指导学员方面有着出色的记录，包括在主要学术中心担任独立的实验室教师。Griffin博士还组建了一个咨询委员会，该委员会在转座因子（Burns博士）、肿瘤免疫学（Sharpe博士）和计算基因组学（货车艾伦博士）方面具有互补的专业知识，并在指导医生-科学家走向独立职业方面拥有丰富的经验。格里芬将进一步补充他的培训与教学课程，以加深他的科学知识，领导力和沟通，并将定期在国家和国际会议上介绍他的工作。Griffin博士提出的研究的主要目标是研究癌细胞中转座因子（TE）沉默和免疫调节的表观遗传机制。Griffin博士提供了初步数据，表明黑色素瘤中的谱系特异性regPAX 3和保守（例如CTCF）转录因子（TF）在SETDB 1扰动后驱动癌细胞中的TE和免疫基因活化。在Griffin博士先前的工作中鉴定的一种新的免疫治疗靶点（Griffin等，Nature 2021）。该提案将研究特定的调控机制，驱动转录反应在黑色素瘤后SETDB 1损失，并将测试的假设，激活潜伏性TE触发随之而来的变化，调节电路和基因座拓扑结构，以驱动免疫激活。这些研究将揭示黑色素瘤中TE和免疫位点的表观遗传调控的基本机制。对其他癌症类型和癌症表观遗传学领域具有广泛的潜在适用性。肿瘤免疫学和免疫疗法。

PROJECT SUMMARY This KOS proposal describes a five-year career development training program in cancer epigenetics and tumor immunology. Dr. Gabriel Griffin has completed clinical training in Hematopathology at Brigham and Women's Hospital and Harvard Medical School (HMS), and will embark on this research program with the goal of training for an independent laboratory-based career investigating basic mechanisms of immune regulation in cancer. In this training program, Dr Griffin will develop further expertise in the study of transposable elements and tumor immunity. and acquire new skills in the areas of genome topology. including the functional analysis of enhancer-promoter loops which will critically enable his future studies. His mentor, Dr. Bradley Bernstein (Chair of Cancer Biology at Dana-Farber Cancer Institute, Professor of Pathology at HMS, Director of the Epigenomics Program at the Broad Institute of MIT and Harvard) is an international leader in the field of cancer epigenomics with an excellent track record in mentoring trainees, including as independent laboratory-based faculty at major academic centers. Dr. Griffin has also assembled an Advisory Committee with complementary expertise in transposable elements (Dr. Burns), tumor immunology (Dr. Sharpe), and computational genomics (Dr. Van Allen), and extensive experience in mentoring physician-scientists to independent careers. Dr. Griffin will further supplement his training with didactic courses to deepen his scientific knowledge, leadership, and communication, and will regularly present his work at national and international meetings. The primary objective of Dr. Griffin's proposed research is to study epigenetic mechanisms of transposable element (TE) silencing and immune regulation in cancer cells. Dr. Griffin provides preliminary data indicating that lineage-specific re g PAX3 in melanoma} and conserved (e.g. CTCF) transcription factors (TFs} drive TE and immune gene activation in cancer cells following perturbation of SETDB1. a novel immunotherapy target identified in Dr Griffin's prior work (Griffin et al., Nature 2021). This proposal will examine the specific regulatory mechanisms that drive transcriptional responses in melanoma following SETDB1 loss, and will test the hypothesis that activation of latent TEs triggers consequent changes in regulatory circuitry and locus topology to drive immune activation. These studies will uncover fundamental mechanisms of epigenetic regulation of TEs and immune loci in melanoma. with broad potential applicability to other cancer types and the fields of of cancer epigenetics. tumor immunology. and immunotherapy.