Determining the Immunological Consequences of DNA Replication Stress Response Defects in Renal Cells Carcinoma to Improve Immunotherapy Outcomes

确定肾细胞癌中 DNA 复制应激反应缺陷的免疫学后果,以改善免疫治疗结果

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT While immunotherapy has shown great promise for robust clinical responses in renal cell carcinoma (RCC), only 1 in 3 patients will see benefit. Current clinical biomarkers, such as mutation burden or PD-L1 expression, have proven to have no predictive capacity in RCC; however, the applicant has recently identified a gene signature of DNA replication stress response (RSR) defects that has predicted immunotherapy response in multiple independent cohorts. This proposal will test the central hypothesis that RSR defects lead to activation of STING signaling to promote sensitivity to immune checkpoint blockade, and that pharmacological induction of RSR defects can sensitize otherwise resistant tumors to immunotherapy. During the K99 mentored phase, the applicant will use highly multiplexed imaging mass cytometry to analyze differences in the immune microenvironment between RSRD-low and RSRD-high patients (Aim 1.1). The applicant will then generated a diverse array of genetically engineered RCC mouse transplant models to enable controlled in vivo studies, and validate that RSR defects are causally linked to immunotherapy response (Aim 1.2). In Aim 2, the applicant will seek to mechanistically understand how RSR defects contribute to immunotherapy response by CRISPR- mediated deletion of STING from an RSRD-high model (Aim 2.1) and in vivo CRISPR screens targeting genes contained within the RSRD signature to ascertain causality (Aim 2.2). The applicant will transition to the R00 independent phase as the CRISPR screen is completed. The CRISPR screen results can serve as a basis for a first R01 submission. Aim 3 will seek to identify pharmacological compounds that will induce RSR defects to sensitize otherwise resistant models to immunotherapy, and will serve as the basis for a second R01 application. This proposal brings together an advisory committee of phenomenal researchers with expertise in DNA damage, immuno-oncology, renal cell carcinoma medical oncology, genetically engineered mouse models, and high- throughput screening to bolster the applicant's skillset in these areas. This will be supplemented by coursework in immunology and responsible conduct of research, as well as additional training to prepare the applicant for leading an independent lab. The environment at MD Anderson, including both the researchers and facilities, makes this one of the few locations where this project could be accomplished. Taken together, this proposal will equip the applicant with the tools to launch by career as a tenure-track faculty member while providing critical insight into immunotherapy for treatment of RCC to advance MD Anderson's goal of Making Cancer History.
项目概要/摘要 虽然免疫疗法在肾细胞癌 (RCC) 中显示出强大的临床反应的巨大前景,但仅 三分之一的患者将受益。目前的临床生物标志物,例如突变负荷或 PD-L1 表达,已 被证明对 RCC 没有预测能力;然而,申请人最近发现了一个基因签名 DNA 复制应激反应 (RSR) 缺陷可预测多种疾病的免疫治疗反应 独立队列。该提案将测试 RSR 缺陷导致 STING 激活的中心假设 信号传导促进对免疫检查点阻断的敏感性,以及 RSR 的药理学诱导 缺陷会使原本具有抗药性的肿瘤对免疫疗法敏感。在K99指导阶段, 申请人将使用高度多重成像质谱流式细胞术来分析免疫的差异 RSRD 低和 RSRD 高患者之间的微环境(目​​标 1.1)。然后申请人将生成一个 多种基因工程 RCC 小鼠移植模型,以实现受控体内研究,以及 验证 RSR 缺陷与免疫治疗反应存在因果关系(目标 1.2)。在目标 2 中,申请人将 寻求机械地了解 RSR 缺陷如何促进 CRISPR 的免疫治疗反应 从 RSRD-high 模型(目标 2.1)介导的 STING 删除和针对基因的体内 CRISPR 筛选 包含在 RSRD 签名中以确定因果关系(目标 2.2)。申请人将过渡到R00 CRISPR 筛选完成后的独立阶段。 CRISPR 筛选结果可以作为 第一个 R01 提交。目标 3 将寻求识别可诱导 RSR 缺陷的药理学化合物 使其他耐药模型对免疫疗法敏感,并将作为第二个 R01 应用的基础。 该提案汇集了一个由具有 DNA 损伤专业知识的杰出研究人员组成的咨询委员会, 免疫肿瘤学、肾细胞癌医学肿瘤学、基因工程小鼠模型和高 吞吐量筛选,以增强申请人在这些领域的技能。这将通过课程作业进行补充 免疫学和负责任的研究行为,以及为申请人做好准备的额外培训 领导一个独立实验室。 MD 安德森的环境,包括研究人员和设施, 使这里成为少数几个可以完成该项目的地点之一。总而言之,该提案将 为申请人提供作为终身教授的职业生涯的工具,同时提供关键的 深入了解肾细胞癌免疫疗法的治疗,以推进 MD 安德森癌症中心“创造癌症历史”的目标。

项目成果

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Daniel James McGrail其他文献

Daniel James McGrail的其他文献

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{{ truncateString('Daniel James McGrail', 18)}}的其他基金

Determining the Immunological Consequences of DNA Replication Stress Response Defects in Renal Cells Carcinoma to Improve Immunotherapy Outcomes
确定肾细胞癌中 DNA 复制应激反应缺陷的免疫学后果,以改善免疫治疗结果
  • 批准号:
    10640407
  • 财政年份:
    2019
  • 资助金额:
    $ 10.33万
  • 项目类别:
Determining the Immunological Consequences of DNA Replication Stress Response Defects in Renal Cells Carcinoma to Improve Immunotherapy Outcomes
确定肾细胞癌中 DNA 复制应激反应缺陷的免疫学后果,以改善免疫治疗结果
  • 批准号:
    10677808
  • 财政年份:
    2019
  • 资助金额:
    $ 10.33万
  • 项目类别:

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