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: 9379331
• 负责人: Juliana Idoyaga
• 金额: $ 31.49万
• 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/9379331
• 关键词: Adjuvant; Affect; Antigens; Automobile Driving; Cancer Patient; Cell Death; Cell physiology; Cells; Cellular biology; Cessation of life; 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; 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; Tumor Antigens; Tumor Immunity; Vaccines; animal imaging; base; clinical practice; compare effectiveness; design; fetal liver kinase-2; genetic signature; image guided radiation therapy; immune function; immunogenic; improved; killings; 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.

项目概要 为了回应 NCI 的挑衅性问题 #11，我们建议调查其作用机制 放射治疗 (RT) 对树突状细胞 (DC) 和其他骨髓细胞功能的影响，以及这些机制的作用 鉴于其在激活和调节新抗原方面的独特作用。 特异性T细胞免疫反应，我们的长期目标是利用DC进行免疫治疗。 我们对 RT 对 DC 亚群和其他骨髓细胞的影响的理解存在根本性的机制差距 这种差距代表了理性的一个重要问题。 放疗与免疫疗法的结合最近在无肿瘤小鼠中的数据表明电离辐射。 (IR) 对 DC 亚群的影响存在差异，导致免疫原性 DC 快速死亡，但不导致耐受性 DC 快速死亡。 此外，IR 改变了 DC 亚群的基因特征，从而改变了它们促进 因此，皮肤暴露于红外线会促进肿瘤的生长。 通过对耐受性 DC 亚群的依赖机制，在 IR 暴露后一天进行移植， 基于这些发现，我们发现肿瘤局部放疗会引起 Treg 的比例发生变化。 DC 亚群通过促进耐受性 DC 的存活和功能而定位于 TME，这反过来又会 我们进一步探究了 IR 对 DC 亚群的这种未经研究的影响。 其他骨髓细胞将显着影响 RT/免疫治疗联合策略的结果。 为了实现特定目标，我们建议对 TME 中的骨髓细胞进行公正的表征 使用新的技术 CyTOF 进行肿瘤靶向放疗和放疗/免疫治疗组合后， 我们将使用类似于患者黑色素瘤驱动突变的小鼠模型，以及图像- 引导放疗允许进行类似于临床使用的分割和立体定向给药方案 我们将把这些特征与肿瘤特异性 T 细胞反应的产生联系起来。 预计从该提案中获得的发现将增强我们目前对 DC 生物学的理解， 响应 RT 的函数，并对组合策略的合理设计产生积极影响。