Determinants of response to cancer immunotherapy

癌症免疫治疗反应的决定因素

基本信息

批准号：
10458030
负责人：
Lawrence Fong
金额：
$ 94.96万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2021-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458030
关键词：
Advanced Malignant Neoplasm Antigens Antitumor Response Basic Science Blood CD4 Positive T Lymphocytes Cancer Patient Cells Clinical Clinical Trials Clone Cells Combination immunotherapy Drug Targeting Future Genomics Goals Immune Immune checkpoint inhibitor Immunosuppression Immunotherapy Knock-out Maps Mediating Modality Neoadjuvant Therapy Operative Surgical Procedures Pathway interactions Patients Positioning Attribute Proteomics Research Resected Resistance T cell receptor repertoire sequencing T-Lymphocyte Therapeutic Translating Translational Research anti-tumor immune response base bench to bedside cancer immunotherapy cancer therapy cell type combinatorial cytotoxic design experience functional plasticity high dimensionality immune checkpoint blockade insight interest mouse model multidisciplinary neoplastic cell novel response single-cell RNA sequencing success tumor

项目摘要

PROJECT SUMMARY/ABSTRACT While immunotherapy is transforming cancer treatment, the majority of patients do not achieve durable responses. We have been studying response and resistance to different immune checkpoint inhibitors and are now poised to propose mechanistic studies aimed at providing an understanding of the immune states and pathways that mediate or inhibit response to immune checkpoint blockade. Using high-dimensional unbiased single-cell RNA-seq (scRNAseq), we can identify both canonical and non-canonical immune effectors that can mediate anti-tumor responses. We believe that non-canonical effectors such as cytotoxic CD4 T cells, which we have recently described, are not effectively triggered by our current treatments. Using the same single-cell approaches, we can identify both known and novel cell types in cancer patients that can mediate immune suppression. In our first objective, we will determine whether combination immunotherapies that include drug(s) targeting specific immunosuppressive cells can enhance the function of these cytotoxic CD4+ T cells. By leveraging neoadjuvant clinical trials where patients receive immunotherapy prior to surgery, we will use single cell genomics and proteomics to define whether these combinations can 1) target the desired immunosuppressive mechanisms, and 2) enhance canonical and/or non-canonical effectors within the resected tumors. We will also use this approach to determine whether we can map these specific cell states into the circulating compartment. The second objective is based on a longstanding interest in our group to define the dynamics of antigen-specific responses. Using single-cell T cell receptor sequencing, we can identify expanded T cell clones as well as follow their localization. In addition to understanding how immunotherapy combinations induce and modulate specific T cell clonotypes within the tumor, we can determine how immunotherapies can induce functional plasticity to desired or undesired states. The third objective builds on our 20 year experience using mouse models to dissect mechanisms underlying response or resistance to immunotherapy. We will determine the functional significance of non-canonical immune effectors using depletion and knock-out strategies. We will also determine how combination immunotherapies can elicit both effective or ineffective anti- tumor immune responses, thereby guiding the design of future clinical trials. In conclusion, our proposal is based on hypothesis-driven bench-to-bedside and bedside-to-bench mechanistic studies with the goal of advancing cancer immunotherapy. With our deep expertise in this field, experience leading multi-disciplinary teams focused on translational research, and a rich network of basic science and clinical collaborators; we are uniquely positioned to succeed in the research plan outlined in this proposal.

项目概要/摘要虽然免疫疗法正在改变癌症治疗，但大多数患者并未实现持久的治疗回应。我们一直在研究对不同免疫检查点抑制剂的反应和耐药性，并且正在研究现在准备提出旨在提供对免疫状态和介导或抑制对免疫检查点封锁反应的途径。使用高维无偏单细胞 RNA 测序 (scRNAseq)，我们可以识别典型和非典型免疫效应子，介导抗肿瘤反应。我们相信非典型效应细胞，例如细胞毒性 CD4 T 细胞，我们最近描述的，我们目前的治疗方法并不能有效地触发。使用相同的单细胞通过这些方法，我们可以识别癌症患者体内能够介导免疫的已知和新型细胞类型抑制。在我们的第一个目标中，我们将确定是否包含药物的联合免疫疗法针对特定的免疫抑制细胞可以增强这些细胞毒性 CD4+ T 细胞的功能。经过利用患者在手术前接受免疫治疗的新辅助临床试验，我们将使用单一细胞基因组学和蛋白质组学来定义这些组合是否可以 1) 靶向所需的免疫抑制机制，2）增强切除区域内的典型和/或非典型效应器肿瘤。我们还将使用这种方法来确定是否可以将这些特定的细胞状态映射到循环室。第二个目标是基于我们小组的长期兴趣来定义抗原特异性反应的动态。使用单细胞 T 细胞受体测序，我们可以识别扩展的 T 细胞克隆并跟踪其定位。除了了解免疫疗法如何组合诱导和调节肿瘤内的特定 T 细胞克隆型，我们可以确定免疫疗法如何发挥作用诱导功能可塑性达到期望或不期望的状态。第三个目标建立在我们 20 年经验的基础上使用小鼠模型来剖析免疫治疗反应或抵抗的机制。我们将使用耗尽和敲除确定非典型免疫效应器的功能意义策略。我们还将确定联合免疫疗法如何引发有效或无效的抗- 肿瘤免疫反应，从而指导未来临床试验的设计。总之，我们的建议基于以假设为驱动的实验室到临床和临床到临床机制研究，目标是推进癌症免疫疗法。凭借我们在该领域的深厚专业知识，拥有领导多学科团队的经验转化研究以及丰富的基础科学和临床合作者网络；我们是独一无二的定位于成功完成本提案中概述的研究计划。