Clonal drivers of resistance to immune checkpoint blockade in liver malignancies

肝脏恶性肿瘤抵抗免疫检查点阻断的克隆驱动因素

基本信息

批准号：
10549797
负责人：
Giannicola Genovese
金额：
$ 18.56万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-12 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549797
关键词：
Address Advanced Malignant Neoplasm Architecture Automobile Driving Bar Codes Behavior Biological CRISPR/Cas technology Cancer Biology Cancer Etiology Cancer Model Cancer Patient Cells Cessation of life Clinical Clonal Evolution Clonal Expansion Clustered Regularly Interspaced Short Palindromic Repeats Cytotoxic Chemotherapy Development Disease Disease Progression Ecosystem Epigenetic Process Epithelium Event Experimental Models Fishes Fluorescence Funding Generations Genetic Genetically Engineered Mouse Genomics Hepatobiliary Heterogeneity Human Human Characteristics Immune Immune Evasion Immune response Immunocompetent Immunomodulators Immunotherapy Kidney Knowledge Libraries Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Metabolic Methods Mission Molecular Mus Nature Nivolumab Oncologist Outcome Pathologic Patients Phase Population Recovery Recurrence Recurrent disease Reporter Research Research Design Resistance Sampling Signal Transduction Sorting Suicide Technology Therapeutic Transplantation Tumor-Derived United States National Institutes of Health Validation adaptive immune response cancer cell cancer therapy cancer type checkpoint modulation chemotherapy design experience human disease immune checkpoint immune checkpoint blockade liver cancer model mortality mosaic multiple omics new technology novel patient subsets pressure response targeted treatment therapy resistant tool tumor weapons

项目摘要

PROJECT SUMMARY Background and relevance to NIH mission. Immune checkpoint blockade based therapy has quickly become the treatment paradigm for several advanced cancer including liver malignancies providing the clinical oncologist with a formidable weapon to achieve dramatic and durable tumor response. The widespread clinical use of modulators of the immune checkpoint, however, has clearly shown that a subset of patients are intrinsically poorly responsive to such treatments, while others might develop recurrent disease after an initial response. While this phenomenon is widely recognized the mechanisms underlying intrinsic and acquired resistance to immune therapy are still poorly understood, posing an urgent need for the development of novel technological tools to study and predict which clones within a tumor will likely drive recurrence. Research design. To investigate the cancer cell intrinsic mechanisms of adaptation and the tumor clonal dynamics in response to immune-checkpoint blockade in an autochthonous experimental model of cancer we will barcode somatic mosaic GEM models of liver cancer to look into the clonal drivers of resistance to immune- checkpoint blockade leveraging a CRISPR-Cas9 based clonal recovery method. Methods. We have generated somatic mosaic cancer models which faithfully recapitulate the biological behavior, the genomic complexity and functional heterogeneity of human disease. To investigate the clonal response to immune therapy malignant cells will be transduced with a dual reporter/suicide cassette barcoded lentiviral library that enables the precise recovery and expansion of any given barcoded clone by using a CRISPR/Cas9 based “fishing” method. These novel technology will be instrumental in the isolation and characterization of those clones/malignant cell populations that are intrinsically prone to evade the immune response or that stochastically acquire the ability to evade the adaptive immune response in the context of immune competent models of cancer. Genetic, molecular and metabolic characterization of such populations will shed light on the mechanisms driving the evasion from immune checkpoint blockade. Ultimately, we will gain fundamental information about clonal dynamics during disease progression in renal malignancies, in addition, by enabling the recovery of single clones and the generation of clonal avatars, this approach would help understanding the relative contribution of intrinsic cell plasticity vs. stochastic genetic events in driving disease recurrence. The technology would eventually demonstrate broader applications in the field of cancer biology and provide novel knowledge and valuable research tools to tackle different cancer types, particularly those characterized by a poor response to immune checkpoints modulation.

项目摘要背景和与NIH任务相关。基于免疫检查点封锁的治疗已迅速成为几种晚期癌症的治疗范例，包括肝恶性肿瘤，提供临床肿瘤学家具有强大的武器，以实现戏剧性和耐用的肿瘤反应。广泛的临床用途但是，免疫检查点的调节剂清楚地表明，一部分患者是本质上的对这种治疗的反应不佳，而其他人则可能在初步反应后患上复发性疾病。虽然这种现象被广泛认识到了内在和获得的抗药性的机制免疫治疗仍然很少了解，迫切需要开发新的技术研究和预测肿瘤中哪些克隆的工具可能会导致复发。研究设计。研究适应和肿瘤克隆的癌细胞内在机制在癌症的自节体实验模型中响应免疫检查封锁的动力学将条形码的肝癌体细胞镶嵌宝石模型来研究具有免疫力的克隆驱动因素利用基于CRISPR-CAS9的克隆恢复方法的检查点封锁。方法。我们已经生成了忠实地概括了生物学行为，基因组复杂性和人类疾病的功能异质性。调查对免疫疗法恶性肿瘤的克隆反应细胞将使用双重记者/自杀盒式盒式慢病毒库转移通过使用基于CRISPR/CAS9的“钓鱼”方法，通过使用给定的条形码克隆的任何给定的条形码克隆恢复和扩展。这些新技术将在这些克隆/恶性细胞的隔离和表征中发挥作用本质上容易发生免疫反应的人群或随机性获得的能力在癌症的免疫能力模型的背景下逃避适应性免疫响应。遗传，分子这种人群的代谢表征将阐明推动逃避的机制免疫检查点封锁。最终，我们将获得有关克隆动态的基本信息另外，肾脏恶性肿瘤中的疾病进展是通过使单个克隆的恢复和克隆化身的产生，这种方法将有助于了解固有细胞的相对贡献可塑性与驱动疾病复发的随机遗传事件。该技术最终将在癌症生物学领域展示广播公司的应用，并提供新颖的知识和价值解决不同癌症类型的研究工具，特别是对免疫反应不良的特征检查点调制。