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: 10005191
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005191
• 关键词: Address; Advanced Malignant Neoplasm; Agonist; Antibodies; Antiviral Agents; 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