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

这一奖项是NSF努力促进癌症生物学基础理解取得重大进展的努力的一部分，通过涉及理论物理、应用数学和计算机科学的多学科研究。胰腺癌是癌症死亡的常见且不断增加的原因。虽然涉及免疫系统的创新策略在治疗许多癌症方面取得了进展，但这些策略迄今对胰腺癌无效。这些肿瘤释放免疫抑制分子，并充当物理屏障，导致免疫细胞渗透和激活减少。最近的研究表明，大剂量的维生素D可以减少免疫抑制，增加免疫细胞在肿瘤中的渗透，为免疫细胞对胰腺癌的有效攻击奠定了基础。这个项目的核心是使用理论建模和对免疫细胞谱系的统计学理解来设计成功的免疫系统对癌症的攻击。在这个项目中，一个由理论物理学家和癌症研究人员组成的团队将共同努力，设计基于免疫系统的量化策略来攻击胰腺癌。将使用新的理论和实验工具来表征胰腺癌肿瘤的免疫环境，并将利用对免疫细胞反应动力学的详细了解来开发创新的干预措施。该项目将专注于量化胰腺导管腺癌鲜为人知的免疫环境。从接受新辅助化疗加大剂量维生素D治疗的患者的肿瘤组织中获得T细胞受体序列、肿瘤外显子和RNA表达，将确定浸润性肿瘤的T细胞是代表独特的还是寡克隆细胞群。平行研究将系统地评估细胞因子的表达和检查点蛋白的表达，以及免疫调节细胞群体的存在。使用理论物理和数学方法的外显子组测序分析将被用来初步洞察肿瘤表达的潜在新抗原。将利用定量模型和分析工具开发针对该癌症的综合平台。这项提案由物理部的生命系统物理学项目和分子和细胞生物科学部的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.