Dissecting the Role of Radiation in Regulation of MHC-I and Neoantigen Presentation

剖析辐射在 MHC-I 和新抗原呈递调节中的作用

• 批准号: 10389117
• 负责人: Chang Su
• 金额: $ 3.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-02 至 2025-12-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389117
• 关键词: Antibodies; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antitumor Response; Autophagocytosis; Bacterial Infections; CRISPR screen; CTLA4 gene; Cancer Burden; Cancer Patient; Cells; Clinical; Clinical Trials; Complex; Custom; Cytotoxic T-Lymphocytes; Data; Distant Metastasis; Down-Regulation; Flow Cytometry; Genes; Genetically Engineered Mouse; Glycoproteins; Goals; Histocompatibility; Histocompatibility Antigens Class I; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immune system; Immunization; Immunotherapy; Ionizing radiation; Knowledge; Local Therapy; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane; Messenger RNA; Mission; Modeling; Mus; Neoplasm Metastasis; Neoplasm Transplantation; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Phase II Clinical Trials; Play; Population; Proteins; Public Health; Radiation; Radiation therapy; Recurrence; Regimen; Regulation; Regulatory Pathway; Research; Research Personnel; Resistance; Role; Soft tissue sarcoma; Solid Neoplasm; Surface; T-Cell Receptor; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Transplantation; Tumor Antigens; Up-Regulation; Viral Antigens; Work; anti-CTLA4; anti-PD-1; anti-PD1 therapy; antigen processing; antitumor effect; cancer cell; cancer therapy; cancer type; cytokine; genome-wide; immune checkpoint blockade; immune resistance; improved; in vivo; innovation; insight; killings; melanoma; mouse model; neoantigens; neoplastic cell; novel; novel strategies; objective response rate; preclinical study; protein expression; receptor; recombinase; response; sarcoma; synergism; transcriptome sequencing; tumor

Abstract: Immunotherapy has recently emerged as a promising new approach to cancer treatment. Durable anti-tumor responses have been achieved with immune checkpoint inhibitors (ICIs) such as anti-PD1 and anti-CTLA4. However, most cancer patients respond poorly to ICIs, including soft tissue sarcoma patients. An important research objective in improving therapy for soft tissue sarcoma patients is to understand pathways that are associated with resistance to ICIs. Downregulation of the antigen presentation pathway has been associated with resistance to ICIs in various cancers. Radiation therapy, on the other hand, has been shown to increase antigen presentation. Although it has been postulated that radiotherapy enhances therapeutic effects of ICIs through upregulation of MHC-I molecules, the regulatory pathway(s) for radiation-induced MHC-I upregulation remains poorly understood. To investigate the role of radiotherapy in modulating tumor antigen presentation, I will use genetically engineered mouse models of autochthonous soft tissue sarcomas to dissect the mechanisms responsible for modulating MHC-I expression after radiation. The long-term goal of this project is to elucidate the mechanisms by which radiotherapy can help to overcome immunotherapy resistance. The primary objective of this proposal is to investigate the underlying pathway through which radiotherapy modulates the MHC-I antigen presentation pathway. The central hypothesis of this study is that radiotherapy upregulates MHC-I expression in soft tissue sarcomas, which increases neoantigen presentation to the immune system and sensitizes tumor cells to cytotoxic T cell killings and ICI treatments. I will test this hypothesis in the following two specific aims: Aim 1: Investigate regulatory networks responsible for MHC-I expression in soft tissue sarcomas. Aim 2: Test whether radiation increases neoantigen presentation on tumor cells and antigen-presenting cells in vivo.

摘要： 免疫疗法最近已成为一种很有前途的癌症治疗新方法。持久的抗肿瘤 已经用免疫检查点抑制剂（ICI）如抗PD 1和抗CTLA 4实现了免疫应答。 然而，大多数癌症患者对ICI反应不佳，包括软组织肉瘤患者。一个重要 改善软组织肉瘤患者治疗的研究目标是了解 与ICIs耐药性有关。抗原呈递途径的下调与 对各种癌症的ICI有抵抗力另一方面，放射治疗已被证明会增加 抗原呈递尽管已经假设放射治疗增强了ICI的治疗效果， 通过MHC-I分子的上调，辐射诱导的MHC-I上调的调节途径 仍然知之甚少。为了研究放射治疗在调节肿瘤抗原呈递中的作用， 将使用本地软组织肉瘤的基因工程小鼠模型来解剖 负责调节辐射后MHC-I表达的机制。 该项目的长期目标是阐明放射治疗有助于克服 免疫治疗抵抗。本提案的主要目的是研究潜在的途径 放射疗法通过其调节MHC-I抗原呈递途径。这个问题的核心假设是 研究表明放射治疗上调了软组织肉瘤中MHC-I的表达， 在某些实施方案中，细胞因子可被呈递给免疫系统，并使肿瘤细胞对细胞毒性T细胞杀伤和ICI治疗敏感。我 将在以下两个具体目标中检验这一假设： 目的1：研究软组织肉瘤中MHC-I表达的调控网络。 目的2：测试放射是否增加肿瘤细胞和抗原呈递细胞上的新抗原呈递， vivo.