Enhancing the antitumor effect of radiation therapy by targeting the cGAS-STING pathway

通过靶向 cGAS-STING 通路增强放射治疗的抗肿瘤作用

• 批准号: 10529042
• 负责人: Yan Fang
• 金额: $ 3.73万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529042
• 关键词: Abscopal effect; Advanced Malignant Neoplasm; Antibodies; Antigen-Presenting Cells; Autophagocytosis; Back; Cancer Vaccine Related Development; Cancer Vaccines; Cell Death; Cell physiology; Cells; Cessation of life; Coculture Techniques; Computational Technique; Cross Presentation; Cytotoxic T-Lymphocytes; Data; Data Analyses; Defect; Disseminated Malignant Neoplasm; Distal; Generations; Goals; Growth; ITGAM gene; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunotherapy; Injections; Interferons; Irradiated tumor; Knowledge; Malignant Neoplasms; Mediating; Modeling; Mus; Mutant Strains Mice; Natural Immunity; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phase; Population; Radiation; Radiation therapy; Research; Research Personnel; Resources; Role; Signal Pathway; Stimulator of Interferon Genes; Technology; Testing; Therapeutic; Transplantation; Treatment outcome; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Work; anti-cancer; anti-tumor immune response; antitumor effect; cancer immunotherapy; cancer prevention; cancer therapy; cell killing; design; experimental study; genomic data; high dimensionality; immune function; improved; in vivo; innate immune sensing; innovation; macrophage; mouse model; neoantigens; neoplastic cell; neutrophil; novel; novel therapeutic intervention; response; single-cell RNA sequencing; skills; targeted treatment; transcriptome; treatment effect; treatment strategy; tumor; tumor DNA; tumor growth; tumor heterogeneity; tumor immunology; tumor microenvironment

Project Summary and Abstract Immunotherapy has achieved promising outcomes in cancer treatments; however, most patients still do not respond to the current therapies. There are several critical gaps in our current knowledge of what types of immune cells exist in the tumor microenvironment and how their presence (or absence) impacts the tumor immune surveillance. My long-term goal is to develop new cancer prevention and treatment approaches through dissecting the diverse immune cells and their roles in the tumor microenvironment. My preliminary studies have identified an enhanced antitumor effect for metastatic cancers by combining radiotherapy with the innate immune sensing pathway activation (the cGAS-cGAMP-STING pathway). This proposal aims to identify novel immune cell populations that contribute to the effective antitumor treatment strategy. The central hypothesis is that specific subsets of immune cells induced by this treatment strategy are the major factors controlling tumor treatment effects. Successful identification of these immune cell populations will improve our understanding of antitumor immunity and cancer immunotherapies. I will test the central hypothesis by pursuing two specific aims: 1) Characterize the immune cell heterogeneity in tumors in response to STING activation (F99 phase); 2) Elucidate the mechanism of abscopal antitumor effects achieved through the combination of cGAMP and radiotherapy (K00 phase). I will pursue these aims using an innovative combination of experimental and computational techniques. I will use unbiased single-cell transcriptome data analysis to identify novel cell populations critical for the tumor treatments and investigate their functions in mouse models. The proposed research is significant because the unbiased genomics data allows me to identify new mechanisms that may have a broad implication in other tumor types and aid in developing new therapeutic strategies. This work will also develop resources that can be used by other researchers in the cancer immunology field. The expected outcome of this work is: 1) identifying novel immune cell populations with antitumor function, 2) offering rational combination strategies to improve antitumor effects, 3) informing the design of cancer vaccines. This project will advance cancer immunology fields by providing new therapeutic strategies for metastatic cancers. In addition, the skills and expertise obtained from both phases will prepare me to become an independent researcher in cancer immunology.

项目概要和摘要 免疫疗法在癌症治疗中取得了有希望的结果;然而，大多数患者仍然没有 对目前的治疗有反应。在我们目前对什么类型的 免疫细胞存在于肿瘤微环境中，以及它们的存在（或不存在）如何影响肿瘤 免疫监视我的长期目标是开发新的癌症预防和治疗方法， 解剖不同的免疫细胞及其在肿瘤微环境中的作用。我的初步研究表明 通过将放射治疗与先天免疫相结合， 传感途径激活（cGAS-cGAMP-STING途径）。该提案旨在确定新的免疫 有助于有效的抗肿瘤治疗策略的细胞群。核心假设是， 由这种治疗策略诱导的特定免疫细胞亚群是控制肿瘤的主要因素 治疗效果这些免疫细胞群的成功鉴定将提高我们对 抗肿瘤免疫和癌症免疫疗法。 我将通过追求两个具体目标来测试中心假设：1）表征免疫细胞的异质性， 肿瘤对STING激活的反应（F99期）; 2）阐明远位抗肿瘤作用的机制 通过cGAMP和放射治疗的组合（K 00期）实现。我将使用一个 实验和计算技术的创新结合。我将使用无偏单细胞 转录组数据分析，以鉴定对肿瘤治疗至关重要的新型细胞群，并研究其 在小鼠模型中的功能。这项拟议中的研究意义重大，因为无偏见的基因组学数据允许 我来确定新的机制，可能有广泛的影响，在其他类型的肿瘤，并帮助发展 新的治疗策略。这项工作还将开发可供其他研究人员使用的资源， 癌症免疫学领域。这项工作的预期结果是：1）鉴定具有以下特征的新的免疫细胞群： 抗肿瘤作用，2）提供合理的组合策略，以提高抗肿瘤作用，3）告知 癌症疫苗的设计。该项目将通过提供新的治疗方法来推进癌症免疫学领域 转移性癌症的治疗策略此外，从这两个阶段获得的技能和专业知识将使我做好准备 成为癌症免疫学的独立研究员