Liberating T-Cell Mediated Immunity to Pancreatic Cancer Using Theoretical Biophysics Analysis

该奖项是美国国家科学基金会努力促进癌症生物学的基本理解的重大进展的一部分，通过多学科研究，涉及理论物理，应用数学和计算机科学的专家。胰腺癌是一种常见的和日益增加的癌症死亡原因。虽然涉及免疫系统的创新策略在许多癌症的治疗中取得了进展，但这些策略迄今为止对胰腺癌无效。这些肿瘤释放免疫抑制分子，并作为物理屏障，导致免疫细胞浸润和激活减少。最近的研究表明，大剂量的维生素D会降低免疫抑制作用，增加肿瘤中的免疫细胞浸润，为有效的免疫细胞攻击胰腺癌奠定基础。该项目的核心是使用理论建模和对免疫细胞库的统计理解来设计成功的免疫系统对癌症的攻击。 在这个项目中，一组理论物理学家和癌症研究人员将共同努力，设计基于免疫系统的定量策略来攻击胰腺癌。新的理论和实验工具将用于表征胰腺癌肿瘤的免疫环境，对免疫细胞反应动力学的详细了解将用于开发创新干预措施。该项目将侧重于量化胰腺导管腺癌的免疫环境。T细胞受体序列库、癌症外显子组和RNA表达将从用新辅助化疗加高剂量维生素D治疗的患者的肿瘤组织获得。将确定浸润患者肿瘤的T细胞是否代表独特或寡克隆细胞群。平行研究将系统地评估细胞因子表达和检查点蛋白的表达，以及免疫调节细胞群的存在。使用理论物理和数学方法的外显子组测序分析将用于获得对肿瘤表达的潜在新抗原的初步了解。定量模型和分析工具将用于开发攻击这种癌症的综合平台。该提案由物理系生命系统物理学项目以及分子和细胞生物科学系系统和合成生物学项目共同资助。

This award is part of the NSF effort to promote significant advances in the fundamental understanding of cancer biology made possible through multidisciplinary research that involves experts in theoretical physics, applied mathematics, and computer science.Pancreatic cancer is a common and increasing cause of cancer death. While innovative strategies involving the immune system have brought progress in the treatment of many cancers, these strategies have to date been ineffective in pancreatic cancer. These tumors release immunosuppressive molecules and act as a physical barrier causing reduced immune cell infiltration and activation. Recently it was shown that large doses of Vitamin D result in reduced immunosuppression and increased immune cell infiltration in tumors, setting the stage for an effective immune cell attack on pancreatic cancer. The heart of this project is the use of theoretical modeling and statistical understanding of immune cell repertoires to design successful immune system attack on the cancer. In this project a team of theoretical physicists and cancer researchers will work together to design quantitative strategies based on the immune system to attack pancreatic cancer. Novel theoretical and experimental tools will be used to characterize the immunological environment of pancreatic cancer tumors and the detailed understanding of the immune cell response dynamics will be used to develop innovative interventions. The project will focus on quantifying the poorly understood immune environment of pancreatic ductal adenocarcinoma. T cell receptor sequence repertoires, the cancer exome, and RNA expression will be obtained from tumor tissue of patients treated with neoadjuvant chemotherapy plus a high dose vitamin D. Whether the T cells infiltrating patient tumors represent unique or oligoclonal cell populations will be determined. Parallel studies will systematically assess cytokine expression and the expression of checkpoint proteins, as well as the presence of immunoregulatory cell populations. Exome sequencing analysis using theoretical physics and mathematical approaches will be used to gain initial insight into potential neo-antigens expressed by tumors. The quantitative models and analysis tools will be used to develop integrated platform for attacking this cancer. This proposal is cofunded by the Physics of Living Systems Program in the Physics Division and the Systems and Synthetic Biology Program in the Molecular and Cellular Biosciences Division.