Mechanisms and strategies to rescue suboptimal T cell priming in colon cancer

挽救结肠癌 T 细胞启动不良的机制和策略

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT I propose to functionally interrogate mechanisms of cancer immune evasion and immunotherapy resistance in powerful new mouse models of colorectal cancer (CRC). Immune checkpoint blockade (ICB) has revolutionized treatment of multiple solid tumor types but is nevertheless ineffective in most cancers. I hypothesize that this is due in part to distinct programs of T cell dysfunction that respond poorly to ICB, such as that programmed by suboptimal T cell priming. While microsatellite instable (MSI) CRC responds remarkably well to ICB, likely due to a high burden of mutation-derived antigens (neoantigens), most CRC (~88%) is microsatellite stable (MSS) and does not respond. However, MSS CRC is characterized by a higher burden of mutations than other solid tumor types that do respond to ICB, like kidney cancer. My own analysis of human MSS CRC sequencing revealed that all tumors expressed at least two clonal neoantigens with strong predicted binding to HLA-I, but that these neoantigens were expressed at significantly lower levels than those in MSI CRC. This suggests that neoantigen expression levels, in addition to burden, may play an important role in the antitumor T cell response. To test this, I developed a colonoscopy-guided orthotopic transplant model of CRC employing isogenic organoids with varying levels of expression of model CD8+ T cell neoantigens. High expression resulted in organoid rejection, while low expression resulted in poor T cell priming with immediate dysfunction and tumor escape. Tumor infiltrating T cells in my low neoantigen-expressing model and human MSS CRC showed signatures of tolerogenic dysfunction, distinct from canonical “exhaustion” and consistent with suboptimal priming. These analyses also identified the orphan nuclear receptor 4A subfamily genes Nr4a1, Nr4a2, and Nr4a3—an exciting new class of T cell checkpoint—as potentially central mediators of this process. Aim 1 will functionally interrogate Nr4a1-3 in T cell priming and dysfunction and investigate their potential as therapeutic targets in CRC. Aim 2 will determine whether existing therapies that boost T cell priming (CD40 agonism, vaccination) can rescue suboptimal T cell priming in CRC and delineate T cell intrinsic and extrinsic mechanisms of efficacy and resistance. The overarching goal of these aims is to deepen our mechanistic understanding of non-canonical T cell dysfunction in CRC and identify new therapeutic strategies to reverse it. This holds substantial promise for the majority of CRC and other cancers that do not respond to ICB and may guide novel combination clinical trials. This proposal is innovative in bringing together cutting-edge mouse models of cancer and advanced tools in immunology. Its completion should bring clarity to the outstanding question of why CRC, the second leading cause of cancer deaths worldwide, is generally nonresponsive to current immunotherapies. The K22 award will help me execute these aims and generate preliminary data that will form a foundation for competitive R01 applications, publications, and a successful independent research program, as well as give me the flexibility to augment my immunology training through NASDC course offerings.
项目总结/摘要 我建议从功能上研究癌症免疫逃避和免疫治疗抵抗的机制 在强大的新的结肠直肠癌(CRC)小鼠模型。免疫检查点阻断(ICB) 它是多种实体瘤类型的革命性治疗,但在大多数癌症中仍然无效。我 假设这部分是由于对ICB反应差的T细胞功能障碍的不同程序, 这是由次优T细胞引发的。而微卫星不稳定(MSI)CRC响应显着 可能由于突变衍生抗原(新抗原)的高负荷,大多数CRC(约88%) 微卫星稳定(MSS),没有反应。然而,MSS CRC的特征在于较高的 与其他实体瘤类型相比,ICB确实对突变有反应,如肾癌。我对人类的分析 MSS CRC测序显示,所有肿瘤表达至少两种克隆性新抗原, 结合HLA-I,但这些新抗原的表达水平明显低于MSI CRC。 这表明,除了负担之外,新抗原表达水平可能在免疫反应中发挥重要作用。 抗肿瘤T细胞反应。为了验证这一点,我开发了一个结肠镜引导下原位移植的CRC模型 使用具有不同水平的模型CD 8 + T细胞新抗原表达的等基因类器官。高 表达导致类器官排斥,而低表达导致T细胞引发不良, 功能障碍和肿瘤逃逸。在我的低新抗原表达模型和人类中的肿瘤浸润T细胞 MSS CRC显示耐受原性功能障碍的特征,与典型的“衰竭”不同,并且一致。 启动效果不佳这些分析还鉴定了孤儿核受体4A亚家族基因Nr 4a 1, Nr 4a 2和Nr 4a 3--一种令人兴奋的新型T细胞检查点--是这一过程的潜在中心介质。 目的1将功能性地询问Nr 4a 1 -3在T细胞引发和功能障碍中的作用,并研究其作为 CRC的治疗靶点。目标2将确定现有的增强T细胞启动(CD 40)的疗法是否 激动、疫苗接种)可以挽救CRC中的次优T细胞引发,并描绘T细胞内在和外在 功效和抗性机制。这些目标的首要目标是深化我们的机制, 了解CRC中非典型T细胞功能障碍,并确定新的治疗策略来逆转它。 这为大多数CRC和其他对ICB无反应的癌症提供了实质性的希望, 指导新组合的临床试验。这项建议是创新的,汇集了尖端的鼠标 癌症模型和先进的免疫学工具。它的完成应能澄清悬而未决的问题, 为什么CRC,世界范围内癌症死亡的第二大原因,通常对 目前的免疫疗法。K22奖将帮助我实现这些目标,并生成初步数据, 将为有竞争力的R 01应用,出版物和成功的独立研究奠定基础 计划,以及给我的灵活性,以增加我的免疫学培训,通过NASDC课程提供。

项目成果

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Peter Maxwell Kienitz Westcott其他文献

Peter Maxwell Kienitz Westcott的其他文献

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{{ truncateString('Peter Maxwell Kienitz Westcott', 18)}}的其他基金

Investigating the not so minor role of the minor isoform Kras4A in cancer
研究次要亚型 Kras4A 在癌症中的重要作用
  • 批准号:
    8596034
  • 财政年份:
    2013
  • 资助金额:
    $ 20.1万
  • 项目类别:
Investigating the not so minor role of the minor isoform Kras4A in cancer
研究次要亚型 Kras4A 在癌症中的重要作用
  • 批准号:
    8716523
  • 财政年份:
    2013
  • 资助金额:
    $ 20.1万
  • 项目类别:

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用于黑色素瘤联合免疫治疗的白蛋白结合肽抗原和双佐剂的淋巴结靶向共递送
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Allosteric Binding in Antibodies and Protein Antigens
抗体和蛋白质抗原的变构结合
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    7684654
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    2008
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Allosteric Binding in Antibodies and Protein Antigens
抗体和蛋白质抗原的变构结合
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Allosteric Binding in Antibodies and Protein Antigens
抗体和蛋白质抗原的变构结合
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Allosteric Binding in Antibodies and Protein Antigens
抗体和蛋白质抗原的变构结合
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Innate Cellular Lectin-Mediated Binding of Xenogeneic Antigens
先天细胞凝集素介导的异种抗原结合
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先天细胞凝集素介导的异种抗原结合
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