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可喜的成果；然而，大多数患者仍然不 对当前的治疗有反应。我们目前对什么类型的了解存在几个关键差距 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。我的长期目标是通过以下方式开发新的癌症预防和治疗方法 剖析不同的免疫细胞及其在肿瘤微环境中的作用。我的初步研究有 通过将放射疗法与先天免疫相结合，确定了对转移性癌症的增强抗肿瘤作用 传感通路激活（cGAS-cGAMP-STING 通路）。该提案旨在识别新型免疫 有助于有效抗肿瘤治疗策略的细胞群。中心假设是 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。成功鉴定这些免疫细胞群将提高我们对 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检验中心假设：1）表征免疫细胞异质性 肿瘤响应 STING 激活（F99 期）； 2）阐明远隔抗肿瘤作用机制 通过cGAMP和放射治疗相结合（K00期）来实现。我将通过以下方式实现这些目标： 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，以确定对肿瘤治疗至关重要的新细胞群并研究它们 小鼠模型中的功能。拟议的研究意义重大，因为无偏见的基因组数据允许 我确定可能对其他肿瘤类型有广泛影响并有助于发展的新机制 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）鉴定新的免疫细胞群 抗肿瘤功能，2）提供合理的组合策略以提高抗肿瘤效果，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的发展 转移性癌症的策略。此外，从这两个阶段获得的技能和专业知识将为我做好准备 成为癌症免疫学的独立研究员。