Project 2: Role of radiation therapy in establishing cancer immunity

项目2：放射治疗在建立癌症免疫力中的作用

• 批准号: 10360424
• 负责人: ANDY J MINN
• 金额: $ 53.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360424
• 关键词: Address; Advanced Malignant Neoplasm; Agonist; Antibodies; Cell physiology; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Complement; Cross-Priming; DNA; Data; Dendritic Cell Pathway; Dendritic Cells; Dendritic cell activation; Double-Stranded RNA; Event; Extinction (Psychology); Goals; Immune; Immune response; Immune signaling; Immune system; Immunologic Markers; Immunotherapy; Infection; Innate Immune System; Interferons; Ligands; Malignant Neoplasms; Mediating; Modeling; Molecular; Nature; Pathway interactions; Patient Selection; Patients; Pattern; Pattern recognition receptor; Photons; Pre-Clinical Model; Property; Proton Radiation; RNA; RNA Polymerase III; Radiation; Radiation therapy; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Somatic Mutation; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Treatment Efficacy; Tumor Immunity; Untranslated RNA; Viral; anti-CTLA4; anti-PD-1; cancer cell; cancer type; exosome; immune checkpoint blockade; immunogenic; immunoregulation; improved; irradiation; mimicry; neoantigens; neoplastic cell; next generation; pathogen; patient biomarkers; potential biomarker; pre-clinical; preclinical study; programs; radiation effect; radiation response; response; success; tumor

SUMMARY Besides cell intrinsic damage to DNA, radiation (RT) can have systemic effects on the immune system. As such, recent evidence indicates that the efficacy of immune checkpoint blockade (ICB) for cancer can be improved by combination strategies that utilized both RT and ICB. However, our understanding of the pathways that RT utilizes to improve immune-mediated tumor response is limited. Moreover, not all cancer types may benefit from ICB with or without RT, likely necessitating additional maneuvers to enhance the efficacy of these treatments for many tumor types. Accumulating data point toward a role for pattern recognition receptors (PRRs) that are normally responsible for sensing pathogen-associated molecular patterns to activate the innate immune system and optimize immune response. RT may similarly promote the engagement of PRR pathways, resulting in activation of dendritic cells (DCs) that facilitate T cell cross-priming. The types of PRRs, the role of PRRs expressed in tumor cells, the nature of the ligands that engage PRRs, and how such events might converge on DC function after RT are not well understood. Therefore, to complement parallel clinical trials that test the combination of RT + αCTLA4 + αPD1 in patients with advanced cancer, this project seeks to investigate how RT mediates immunomodulatory effects through PRRs and how these signaling events get relayed to DCs to enhance the T cell repertoire. In order to expand the types of cancers that may benefit from RT + ICB, this proposal also examines how engagement of CD40 can non- redundantly activating DCs to further improve response particularly for poorly immunogenic tumors. Thus, by understanding the immunomodulatory mechanism of action of RT, its limitations, and ways to break through therapeutic barriers, our goal is to broaden the efficacy of RT + ICB to more patients in next generation clinical trials.

总结 除了细胞对DNA的内在损伤外，辐射（RT）还可对免疫系统产生全身性影响。作为 因此，最近的证据表明，免疫检查点阻断（ICB）对癌症的疗效可能是 通过使用RT和ICB的组合策略来改善。然而，我们对 RT用于改善免疫介导的肿瘤应答的途径是有限的。此外，并非所有癌症 有或没有RT的洲际弹道导弹都可能对这些类型的导弹有利，可能需要额外的机动来增强洲际弹道导弹的机动性。 这些治疗对许多肿瘤类型的疗效。为模式的角色积累数据点 识别受体（PRR）通常负责感测病原体相关分子， 激活先天免疫系统和优化免疫反应的模式。RT可以类似地促进 PRR通路的参与，导致促进T细胞交叉致敏的树突状细胞（DC）的活化。 PRR的类型，PRR在肿瘤细胞中表达的作用，参与PRR的配体的性质， 以及这些事件如何在RT之后收敛于DC函数还没有很好地理解。因此 补充平行临床试验，测试RT + αCTLA4 + αPD1联合治疗晚期乳腺癌患者 该项目旨在研究RT如何通过PRR介导免疫调节作用，以及如何 这些信号传导事件被传递到DC以增强T细胞库。为了扩大 可能受益于RT + ICB的癌症，该提案还研究了CD40的参与如何能够非 冗余激活DC以进一步改善应答，特别是对于免疫原性差的肿瘤。因此，由 了解RT的免疫调节作用机制，其局限性，以及突破的方法 治疗障碍，我们的目标是在下一代临床中将RT + ICB的疗效扩大到更多患者 审判