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

项目总结 尽管化疗、放疗和手术，未分化多形性肉瘤(UPS)患者 常患不治之症复发。免疫检查点阻断是一种很有前途的新疗法 促进T细胞介导的抗肿瘤免疫的UPS患者的途径。尽管如此，大多数人 患者不会从中受益。放射治疗(RT)是UPS术前治疗的基石，可以煽动 T细胞抗肿瘤反应并与免疫检查点阻断协同作用。但RT也会导致 募集免疫抑制、亲肿瘤的髓系细胞，以抑制抗肿瘤T细胞反应。这是 尤其与UPS有关，UPS的特点是髓系细胞浸润活跃。候选人 假设RT诱导的髓系细胞重新编程为抗原递呈的促炎细胞 表型可促进UPS患者T细胞介导的抗肿瘤免疫。 为了验证这一假设，候选人提出了使用BO-112的研究，BO-112是一种人工合成的纳米复合体版本 Poly I：C激活在髓系细胞中高度活跃的双链RNA传感通路。这些 研究将在UPS小鼠模型(AIM 1)和UPS患者(AIM 2)中进行。在目标1中， 候选人将确定BO-112对RT-112的命运、表型和免疫调节功能的影响 诱导髓系细胞。在目标2中，候选人评估BO-112、RT和抗PD1免疫的能力 检查点阻断以重塑UPS的髓系隔间并激发抗肿瘤T细胞反应 参加机会之窗1期临床试验的患者。这些研究将为我们提供对 RT诱导的髓系细胞亚群的可塑性及其在T细胞介导的抗肿瘤免疫中的作用 对BO-112的回应。 这位候选人是加州大学洛杉矶分校的放射肿瘤学助理教授，专门从事治疗 肉瘤。他在肿瘤免疫学和癌症免疫疗法方面的科学记录突出了他的 致力于这一领域的学术事业。候选人的时间受到保护，用于研究和职业生涯 开发(80%的努力)，他有完成所需的空间、设备、人员和资源 建议进行的研究。与他的导师安东尼·里巴斯博士和共同导师威廉·麦克布莱德博士一起， 应聘者制定了全面的职业发展和培训计划，将在以下方面积累专业知识 四个领域：(1)髓系细胞生物学和可塑性，(2)遗传小鼠模型作为研究肉瘤和 免疫系统，(3)高维单细胞表型和转录的分析和解释 数据，以及(4)进行翻译阶段1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生涯过渡--从板凳到板凳 床边研究，重点是利用翻译免疫学来改变患者的护理 得了肉瘤。

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.