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.

项目概要背景和与 NIH 使命的相关性基于免疫检查点阻断的治疗已迅速成为主流。为临床肿瘤学家提供包括肝癌在内的多种晚期癌症的治疗范例具有实现显着且持久的肿瘤反应的强大武器。然而，免疫检查点调节剂已经清楚地表明，一部分患者本质上是对此类治疗反应不佳，而其他人可能在初次反应后出现复发性疾病。虽然这种现象已被广泛认可，但内在的和获得性的抵抗力背后的机制免疫疗法仍然知之甚少，迫切需要开发新技术研究和预测肿瘤内哪些克隆可能导致复发的工具。研究设计。研究癌细胞的内在适应机制和肿瘤克隆。我们在癌症的本地实验模型中对免疫检查点封锁的反应动力学将对肝癌体细胞嵌合体 GEM 模型进行条形码编码，以研究免疫抵抗的克隆驱动因素我们已经生成了利用基于 CRISPR-Cas9 的克隆恢复方法的检查点封锁。体细胞镶嵌癌症模型忠实地再现了生物学行为、基因组复杂性和研究人类疾病的功能异质性对免疫治疗的克隆反应。细胞将用双报告基因/自杀盒条形码慢病毒文库转导，从而实现精确的转导使用基于 CRISPR/Cas9 的“钓鱼”方法恢复和扩展任何给定的条形码克隆。新技术将有助于这些克隆/恶性细胞的分离和表征本质上容易逃避免疫反应或随机获得免疫反应能力的人群在癌症的免疫能力模型中逃避适应性免疫反应。这些群体的代谢特征将揭示驱动逃避的机制最终，我们将获得有关克隆动态的基本信息。此外，通过实现单克隆的恢复和克隆化身的生成，这种方法将有助于理解内在细胞的相对贡献可塑性与随机遗传事件在驱动疾病复发方面的关系最终将得到解决。展示在癌症生物学领域更广泛的应用，并提供新颖的知识和有价值的研究工具来应对不同类型的癌症，特别是那些对免疫反应较差的癌症检查点调制。