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: 10818003
• 负责人: Benjamin Izar
• 金额: $ 14.49万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818003
• 关键词: Academic Medical Centers; Advanced Malignant Neoplasm; Aftercare; Applications Grants; Back; Biological; Biopsy; Cells; Clear cell renal cell carcinoma; Clinical; Clinical Trials; Clonality; Combined Modality Therapy; Data Set; Disease; Dose; Drug resistance; Endothelial Growth Factors Receptor; Evaluation; Extrahepatic; Freezing; Fresh Tissue; Funding; Genomic approach; Genomics; Goals; Grant; Image; Immune checkpoint inhibitor; Immunofluorescence Immunologic; Immunotherapy; Infiltration; Institution; Interleukin-2; Laboratories; Malignant Neoplasms; Malignant neoplasm of lung; Melanoma Cell; Metastatic Melanoma; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Methods; Modeling; Molecular; Myeloid-derived suppressor cells; Nivolumab; Outcome; Patient Care; Patient Selection; Patients; Pharmaceutical Preparations; Preclinical Testing; RNA; Resistance; Resolution; Role; Site; Specimen; Structure; T cell clonality; T cell receptor repertoire sequencing; T-Cell Receptor; TNFSF15 gene; Technology; Testing; Therapeutic; Tissues; Toxic effect; Vascular Endothelial Growth Factors; Work; cancer cell; cancer immunotherapy; checkpoint therapy; clinically relevant; cohort; combinatorial; complex data; computer framework; cytotoxic CD8 T cells; experience; genome sequencing; immune cell infiltrate; improved; inhibitor; inhibitor therapy; multimodal data; multimodality; novel; patient stratification; predicting response; programs; resistance mechanism; response; spatiotemporal; transcriptome sequencing; tumor; tumor microenvironment; whole genome

PROJECT SUMMARY Cancer immunotherapies have revolutionized the therapy of many cancers, including metastatic melanoma and clear cell renal cell carcinoma (ccRCC). Dating back 30 years, the first cancer immunotherapy, high-dose interleukin-2, was successfully tested in melanoma and ccRCC and provided a first proof-of-concept of a transformative therapeutic potential.1-3 In the last decade, melanoma and ccRCC have represented archetypical diseases, in which a portion of patients experience durable responses to novel immunotherapies, such as immune checkpoint inhibitors (ICI), and these observations frequently extrapolated to other cancers as well (e.g., lung cancer). 4-8 However, most patients do not response to ICI and the underlying mechanisms are unclear. In our initially funded grant (R37CA258829), we explore the role of liver metastasis and their role in conferring resistance to ICI, both locally and in concurrent metastatic sites (e.g., lung metastases). We leverage cutting-edge models and technologies, including single-cell genomics, to dissect this clinically relevant predictor for ICI resistance, and explore opportunities for pre- clinical testing of combination therapies that may help overcoming resistance to ICI. In the current proposal, we will expand on these initial studies and study molecular predictors of response and resistance in patients with metastatic ccRCC who are treated with a combination of ICI and inhibitors of vascular endothelial growth factor receptors (VEGFR). For this purpose, we have collected paired snap-frozen tissue specimens from patients before therapy and after a course of ICI and VEGFR inhibitor therapy. In preliminary studies, we applied cutting-edge technologies developed in our laboratory to enable multi-modal single-cell genomics from frozen tissues achieving excellent technical quality. Furthermore, we established panels for multiplexed immunofluorescence (mIF) on matching tissues. In Aim 1, we will perform mIF on determining spatio-temporal effects of ICI + VEGFR inhibitor therapy, and correlate changes in immune infiltrates with clinical outcomes. In Aim 2, we will perform multi-modal single-cell genomics, including RNA-sequencing and T cell receptor sequencing (TCR) to determine both cancer cell intrinsic and extrinsic molecular and clonal correlates of response and resistance at single-cell resolution. Together with the proposed work in the initial grant application, this supplement will further enhance our understanding of molecular and cellular correlates of response and resistance to immunotherapies.

项目摘要 癌症免疫疗法彻底改变了许多癌症的治疗，包括转移 黑色素瘤和透明细胞肾细胞癌（CCRCC）。可以追溯到30年，第一个癌症 免疫疗法，大剂量白介素2在黑色素瘤和CCRCC和 提供了转化性治疗潜力的第一个概念证明。1-3在过去十年中， 黑色素瘤和CCRC已代表了原型疾病，其中一部分患者 体验对新型免疫疗法的持久反应，例如免疫检查点抑制剂 （ICI），这些观察结果也经常被推断到其他癌症（例如肺癌）。 4-8然而，大多数患者对ICI没有反应，并且基本机制尚不清楚。 在我们最初资助的赠款（R37CA258829）中，我们探讨了肝转移的作用及其作用 在局部和并发转移性位点赋予对ICI的抗性（例如，肺 转移）。我们利用尖端的模型和技术，包括单细胞基因组学， 剖析ICI耐药性的临床相关预测因子，并探索预先的机会 联合疗法的临床测试可能有助于克服对ICI的抗性。在电流中 提案，我们将扩展这些初步研究并研究反应的分子预测指标和 通过ICI和ICI和 血管内皮生长因子受体（VEGFR）的抑制剂。为此，我们有 在治疗前和一段时间后，从患者那里收集了来自患者的配对的快速冻结组织标本 ICI和VEGFR抑制剂疗法。在初步研究中，我们应用了尖端技术 在我们的实验室中开发，以使来自冷冻组织的多模式单细胞基因组学 达到出色的技术质量。此外，我们建立了用于多路复用的面板 匹配组织上的免疫荧光（MIF）。在AIM 1中，我们将执行MIF确定 ICI + VEGFR抑制剂治疗的时空作用，并与免疫变化相关 浸润临床结果。在AIM 2中，我们将执行多模式的单细胞基因组学， 包括RNA测序和T细胞受体测序（TCR）以确定两个癌细胞 单细胞的固有和外在分子和克隆相关性 解决。与初始赠款申请中的拟议工作一起，该补充剂将 进一步增强了我们对分子和细胞反应和细胞相关的理解 抵抗免疫疗法。