Effect of radiotherapy on dendritic cell subsets: implications for immunotherapy

放射治疗对树突状细胞亚群的影响：对免疫治疗的影响

• 批准号: 9752249
• 负责人: Juliana Idoyaga
• 金额: $ 30.56万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752249
• 关键词: Adjuvant; Affect; Antigens; Antitumor Response; Automobile Driving; Cancer Patient; Cell Death; Cell physiology; Cells; Cellular biology; Cessation of life; Combination immunotherapy; Complex; Cytometry; Data; Dendritic Cells; Disease; Effectiveness; Fractionation; Generations; Genes; Goals; Growth Factor; Immune response; Immunity; Immunomodulators; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Ionizing radiation; Laboratories; Lead; Ligands; Malignant Neoplasms; Mediating; Minority; Modeling; Mus; Mutation; Myeloid Cells; Neoplasm Transplantation; Outcome; Patient imaging; Patients; Phagocytosis; Poly I-C; Predisposition; Radiation exposure; Radiation therapy; Regulatory T-Lymphocyte; Role; Scheme; Skin; System; T cell response; T-Cell Activation; T-Lymphocyte; Targeted Radiotherapy; Technology; Testing; Transplantation; Tumor Antigens; Tumor Immunity; Vaccines; animal imaging; antigen-specific T cells; base; clinical practice; compare effectiveness; design; fetal liver kinase-2; genetic signature; image guided radiation therapy; immune function; immunogenic; improved; melanoma; mouse model; neoplastic cell; novel; potential biomarker; programs; radioresistant; response; standard of care; synergism; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY In response to NCI’s Provocative Question #11, we propose to investigate the mechanisms of action of radiotherapy (RT) on the function of dendritic cells (DCs) and other myeloid cells, and how these mechanisms affect the efficacy of immunotherapies. Given their unique role in activating and modulating new antigen- specific T cell immune responses, our long-term goal is to harness DCs for immunotherapy. Currently, there is a fundamental mechanistic gap in our understanding of the effect of RT on DC subsets and other myeloid cells localized in the tumor microenvironment (TME). This gap represents an important problem for the rational combination of RT with immunotherapies. Recent data in tumor-free mice demonstrated that ionizing radiation (IR) differentially affects DC subsets, causing the rapid death of immunogenic but not tolerogenic DCs. Furthermore, IR changes the gene signature of DC subsets and, consequently, their capacity to promote antigen-specific regulatory T cells (Tregs). Therefore, exposure of skin to IR promotes the growth of tumors transplanted one-day post-IR exposure through a mechanism dependent on tolerogenic DC subsets and Tregs. Based on these findings, we hypothesize that tumor-localized RT will induce a shift in the proportion of DC subsets localized in the TME by promoting the survival and function of tolerogenic DCs, which in turn will induce T cell-mediated tolerance. We further hypothesize that this unstudied effect of IR on DC subsets and other myeloid cells will significantly impact the outcome of RT/immunotherapy combination strategies. In three specific aims, we propose to perform an unbiased characterization of myeloid cells localized in the TME following tumor-targeted RT and RT/immunotherapy combinations using newly available technology, CyTOF, and RNA-seq. We will use mouse models that resemble melanoma-driving mutations in patients, and image- guided RT that allows for fractionation and stereotactic delivery schemes similar to those used in clinical practice. We will correlate these characterizations with the generation of tumor-specific T cell responses. We anticipate that findings obtained from this proposal will enhance our current understanding of DC biology and function in response to RT, and positively impact the rational design of combination strategies.

项目摘要 为了回应NCI的挑衅性问题＃11，我们建议调查作用机制 树突状细胞（DC）和其他髓样细胞功能的放射疗法（RT）以及这些机制如何 影响免疫疗法的效率。考虑到它们在激活和调节新抗原方面的独特作用 特定的T细胞免疫调剂，我们的长期目标是利用DC进行免疫疗法。目前，有 我们对RT对DC子集和其他髓样细胞的影响的理解的基本机械差距 位于肿瘤微环境（TME）中。这个差距代表了理性的重要问题 RT与免疫疗法的组合。无肿瘤小鼠的最新数据表明电离辐射 （IR）差异影响DC子集，从而导致免疫原性但耐受性DC的快速死亡。 此外，IR改变了DC子集的基因特征，因此，它们的促进能力 抗原特异性调节T细胞（Tregs）。因此，皮肤暴露于IR会促进肿瘤的生长 通过基于耐受性DC子集和 Tregs。基于这些发现，我们假设肿瘤定位的RT将导致比例的变化 DC子集通过促进耐受性DC的生存和功能来定位于TME，而这又将 诱导T细胞介导的耐受性。我们进一步假设，IR对DC子集和 其他髓样细胞将显着影响RT/免疫疗法组合策略的结果。三分 具体目的，我们建议对TME中的髓样细胞进行公正的表征 使用新近可用的技术Cytof，遵循肿瘤靶向肿瘤的RT和RT/免疫疗法组合 和RNA-seq。我们将使用类似于患者黑色素瘤突变的小鼠模型，以及图像 引导的RT允许分馏和与临床类似的立体定向输送方案 实践。我们将将这些特征与肿瘤特异性T细胞反应的产生相关联。我们 预计从该提案中获得的发现将增强我们对DC生物学的当前理解和 响应RT的功能，并积极影响组合策略的合理设计。