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

• 批准号: 10368974
• 负责人: Benjamin Izar
• 金额: $ 43.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10368974
• 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; 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; Tumor-infiltrating immune cells; Variant; Xenograft Model; advanced disease; cancer cell; cancer immunotherapy; cell motility; cell type; cohort; design; drug development; exome; experimental study; gene product; 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

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.

项目摘要 在过去的三十年中，黑色素瘤的发病率增加了一倍，预计将超过100,000例 美国在2020年。2019年美国有近7,000人死于黑色素瘤。黑色素瘤的倾向很强 通过淋巴和血源性路线传播。转移的最常见部位包括淋巴 节点，肺，肝脏和大脑。尽管新颖的疗法，例如免疫疗法，已经提高了 转移性疾病的患者，转移性模式会影响对这种疗法的反应。尤其， 肝脏转移的患者对免疫检查点的反应较低和存活率较低 与其他器官的转移患者相比，抑制剂与其他器官相比。肝转移的分子基础 发育以及对药物反应和抗药性的影响知之甚少。这部分是由于有限的 类似于患者的转移模式的临床前模型，基因组的稀疏性 人肝转移性病变的表征。该建议的目的是确定黑色素瘤的驱动因素 肝转移（MLM）和对免疫疗法的抗性机制。为此，我们 表征并使用了一种新型的合成小鼠模型，该模型忠实地概括了基因组，转移和 患者看到的反应模式。我们进行了大规模的体内CRISPR-CAS9屏幕，并确定了 促进MLM发展的扰动，但不是原发性肿瘤生长或转移到其他器官 站点。在该提案的第一个目的中，我们阐明了促进MLM的细胞固有信号传导机制。下一个， 使用集成的高应成像，免疫促进和单细胞测序，我们确定免疫 MLM和并发肺转移的浸润以及免疫区室如何影响对 临床使用的免疫疗法。最后，我们组装了大量的来自肝转移的患者活检 以及来自其他器官部位的并发转移以及外周血单核细胞（PBMC） 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景观 MLM的信号传导机制和免疫环境及其对免疫疗法反应的影响 并有潜力确定基本原理药物开发的新途径。