Targeting Radiation-Induced Myeloid Cells to Promote T cell Immunity in Undifferentiated Pleomorphic Sarcoma

项目摘要 尽管化疗，放疗和手术，未分化多形性肉瘤（UPS）患者， 经常患不治之症复发。免疫检查点阻断是一种有前途的新治疗方法 这种方法可以促进T细胞介导的抗肿瘤免疫。尽管如此，大多数 患者没有受益。放射治疗（RT）是UPS术前治疗的基石， T细胞抗肿瘤应答并与免疫检查点阻断协同作用。但RT也可能导致 募集免疫抑制性的、抑制抗肿瘤T细胞应答的前肿瘤骨髓细胞。这是 在UPS中尤其相关，其特征在于活跃的骨髓细胞浸润。候选 假设将RT诱导的骨髓细胞重编程为抗原呈递、促炎性细胞， 表型将促进UPS中T细胞介导的抗肿瘤免疫。 为了调查这一假设，候选人提出了使用BO-112的研究，BO-112是一种合成的纳米复合物， poly I：C，其激活双链RNA传感途径，该途径在骨髓细胞中高度活跃。这些 将在UPS的鼠模型（目标1）以及UPS患者（目标2）中进行研究。在目标1中， 候选人将确定BO-112对RT-12的命运、表型和免疫调节功能的影响。 诱导骨髓细胞。在目标2中，候选人评估BO-112、RT和抗PD 1免疫的能力 检查点阻断以重塑骨髓腔室并激发UPS中的抗肿瘤T细胞反应 参与机会之窗1期临床试验的患者。这些研究将提供关键的洞察力， RT诱导的骨髓亚群的可塑性，以及它们在T细胞介导的抗肿瘤免疫中的作用，特别是在 回复BO-112 该候选人是加州大学洛杉矶分校放射肿瘤学助理教授，专门治疗 肉瘤。他在肿瘤免疫学和癌症免疫治疗方面的科学记录突出了他的 致力于这一领域的学术生涯。候选人的时间是保护的研究和职业生涯 开发（80%的努力），他有必要的空间，设备，人员和资源来完成 建议的研究。沿着他的导师Antoni Ribas博士和共同导师William McBride博士， 候选人已经制定了全面的职业发展和培训计划，将建立专业知识， 四个领域：（1）骨髓细胞生物学和可塑性，（2）遗传小鼠模型作为研究肉瘤的工具， 免疫系统，（3）分析和解释高维单细胞表型和转录组学 数据，以及（4）进行转化1期临床试验。这些职业发展活动将支持 完成提案，并促进向独立的科学职业过渡， 床边研究，重点是利用转化免疫学来改变患者的护理 肉瘤。

PROJECT SUMMARY Despite chemotherapy, radiation and surgery, patients with undifferentiated pleomorphic sarcoma (UPS) frequently suffer incurable disease relapse. Immune checkpoint blockade is a promising new therapeutic approach for patients with UPS which promotes T cell mediated anti-tumor immunity. Still, the majority of patients do not benefit. Radiation therapy (RT), a cornerstone of preoperative treatment of UPS, can instigate T cell anti-tumor responses and synergize with immune checkpoint blockade. But RT can also result in the recruitment of immunosuppressive, pro-tumor myeloid cells that restrain anti-tumor T cell responses. This is particularly relevant in UPS, which is characterized by a brisk myeloid cell infiltrate. The candidate hypothesizes that reprogramming RT-induced myeloid cells toward an antigen-presenting, pro-inflammatory phenotype will promote T cell mediated anti-tumor immunity in UPS. To investigate the hypothesis the candidate proposes studies using BO-112, a synthetic nanoplexed version of poly I:C that activates double-stranded RNA sensing pathways, which are highly active in myeloid cells. These studies will be conducted in murine models of UPS (Aim 1) as well as in UPS patients (Aim 2). In Aim 1, the candidate will determine the impact of BO-112 on the fate, phenotype and immunomodulatory function of RT- induced myeloid cells. In Aim 2, the candidate evaluates the capacity of BO-112, RT, and anti-PD1 immune checkpoint blockade to remodel the myeloid compartment and instigate anti-tumor T cell responses in UPS patients enrolled on a window of opportunity phase 1 clinical trial. These studies will provide key insight into plasticity of RT-induced myeloid subsets, and their role in T cell mediated anti-tumor immunity, especially in response to BO-112. The candidate is an Assistant Professor in Radiation Oncology at UCLA specializing in the treatment of sarcoma. His scientific track record in tumor immunology and cancer immunotherapy highlights his commitment to an academic career in this field. The candidate's time is protected for research and career development (80% effort), and he has the space, equipment, personnel and resources necessary to complete the proposed studies. Along with his mentor, Dr. Antoni Ribas, and co-mentor, Dr. William McBride, the candidate has developed a comprehensive career development and training plan that will build expertise in four areas: (1) myeloid cell biology and plasticity, (2) genetic mouse models as tools to study sarcoma and the immune system, (3) analysis and interpretation of high-dimensional single cell phenotyping and transcriptomic data, and (4) conduct of a translational phase 1 clinical trial. These career development activities will support completion of the proposal and facilitate the transition to an independent scientific career conducting bench-to- bedside research, with an emphasis on leveraging translational immunology to transform the care of patients with sarcoma.