Mechanisms of liver metastasis and associated resistance to immunotherapy

肝转移的机制和相关的免疫治疗耐药性

基本信息

批准号：
10593044
负责人：
Benjamin Izar
金额：
$ 39.7万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-09 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593044
关键词：
Animals Antibodies Biological Markers Biopsy Brain CD4 Positive T Lymphocytes CD8B1 gene CRISPR screen CRISPR/Cas technology Cell physiology Cells Cellular Metabolic Process Clinical Communities Dependence Development Disease Disseminated Malignant Neoplasm Drug Design Drug resistance Environment Flow Cytometry Frequencies Functional disorder Genetic Genome engineering Genomics Glucose Goals Hematogenous Human Image Immune Immune System Diseases Immune checkpoint inhibitor Immunotherapy Impairment Incidence Insulin Insulin Receptor Knock-out Lesion Liver Lung Lymphatic Malignant Neoplasms Measurement Mediating Melanoma Cell Metastatic Melanoma Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Methodology Methods Modeling Molecular Mus Mutation Neoplasm Metastasis Organ PI3K/AKT PIK3CG gene Pancreas Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacotherapy Phosphorylation Physiological Population Pre-Clinical Model Primary Neoplasm Prognosis Proto-Oncogene Proteins c-akt Research Resistance Role Route Signal Transduction Site Survival Rate T-Lymphocyte Testing Variant Xenograft Model advanced disease cancer cell cancer immunotherapy cell motility cell type cohort design drug development exome experimental study gene product immune cell infiltrate improved in vivo inhibitor innovation insulin signaling liver biopsy liver development lymph nodes melanoma metabolomics mouse model multiplexed imaging neoplasm resource novel novel therapeutics phosphoproteomics response sample collection single cell sequencing single-cell RNA sequencing transcriptomics treatment response tumor growth

项目摘要

PROJECT SUMMARY The incidence of melanoma has doubled in the last three decades and is projected to exceed 100,000 cases in the US in 2020. Almost 7,000 people died of melanoma in the US in 2019. Melanoma has a strong propensity to spread both via lymphatic and hematogenous routes. The most common sites of metastasis include lymph nodes, lung, liver and brain. Although novel therapies, such as immunotherapies have improved survival of patients with metastatic disease, metastatic patterns can influence responses to such therapies. In particular, patients with metastases to the liver have a lower response and survival rates in response to immune checkpoint inhibitors compared to patients with metastases to other organs. The molecular underpinnings of liver metastasis development and the impact on drug response and resistance are poorly understood. This is in part due to limited pre-clinical models that resembles metastatic patterns seen in patients, and a sparsity of genomic characterization of human liver metastatic lesions. The goal of this proposal is to determine drivers of melanoma liver metastasis (MLM) and mechanisms of associated resistance to immunotherapies. For this purpose, we characterized and used a novel syngeneic mouse model that faithfully recapitulates genomic, metastatic and response patterns seen in patients. We performed a large-scale in vivo CRISPR-Cas9 screen and identified perturbations that promote development of MLM, but not primary tumor growth or metastasis to other organ sites. In the first aim of this proposal, we elucidate the cell intrinsic signaling mechanisms promoting MLM. Next, using integrated high-plex imaging, immune-profiling and single-cell sequencing, we determine the immune infiltrates of MLM and concurrent lung metastases and how the immune compartment impacts the response to clinically used immunotherapies. Finally, we assembled a large cohort of patient biopsies from liver metastases and concurrent metastases from other organ sites as well as peripheral blood mononuclear cells (PBMCs) for genomic and immune profiling. Together, these studies will provide a landscape of genomic determinants, signaling mechanisms and immune environments of MLM and their impact on responses to immunotherapies and have the potential to identify novel avenues for rationale drug development.

项目概要过去三十年中，黑色素瘤的发病率翻了一番，预计在 2020 年将超过 10 万例 2020 年美国。2019 年美国有近 7,000 人死于黑色素瘤。黑色素瘤有很强的倾向通过淋巴和血行途径传播。最常见的转移部位包括淋巴淋巴结、肺、肝和脑。尽管免疫疗法等新疗法提高了患者的生存率患有转移性疾病的患者，转移模式会影响对此类疗法的反应。尤其，肝转移患者对免疫检查点的反应和生存率较低抑制剂与其他器官转移的患者进行比较。肝转移的分子基础人们对药物反应和耐药性的发展及其影响知之甚少。这部分是由于有限类似于患者转移模式的临床前模型，以及基因组的稀疏性人类肝脏转移病灶的特征。该提案的目标是确定黑色素瘤的驱动因素肝转移（MLM）和免疫疗法相关耐药机制。为此，我们表征并使用了一种新颖的同基因小鼠模型，该模型忠实地再现了基因组、转移和患者中观察到的反应模式。我们进行了大规模体内 CRISPR-Cas9 筛选并鉴定促进 MLM 发展的扰动，但不会促进原发性肿瘤生长或转移至其他器官网站。在本提案的第一个目标中，我们阐明了促进 MLM 的细胞内在信号传导机制。下一个，使用集成的高重成像、免疫分析和单细胞测序，我们确定了免疫 MLM 浸润和并发肺转移以及免疫区室如何影响对 MLM 的反应临床上使用的免疫疗法。最后，我们收集了大量肝转移患者的活检样本以及来自其他器官部位以及外周血单核细胞 (PBMC) 的并发转移基因组和免疫分析。这些研究将共同提供基因组决定因素的全景图， MLM 的信号机制和免疫环境及其对免疫疗法反应的影响并有潜力确定药物开发的新途径。