Contribution of the Inflammasome to Radiation Response in Pancreatic Cancer

炎症小体对胰腺癌放射反应的贡献

• 批准号: 10559478
• 负责人: Terry R Medler
• 金额: $ 16.2万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559478
• 关键词: Adjuvant; Antitumor Response; Binding; Bioinformatics; Biology; CASP1 gene; CD8-Positive T-Lymphocytes; Cells; Cellular Stress; Characteristics; Chronic; Colitis associated colorectal cancer; Communication; Cytotoxic Chemotherapy; Data; Data Set; Dendritic Cells; Development; Fellowship; Funding; Gene Expression Profile; Genes; Genetic Transcription; Goals; Heterodimerization; Homeostasis; Homo; IL18 gene; IL1R1 gene; Immune; Immune response; Immune system; Immunosuppression; Immunotherapy; In Vitro; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; K22 Award; Knockout Mice; Laboratories; Leukocytes; Ligation; Lymphoid Cell; MERTK gene; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator; Molecular; Mus; Mutation; Myeloid Cells; Natural Immunity; Nature; Outcome; Pathology; Pathway interactions; Patients; Pattern; Phagocytes; Phenotype; Postdoctoral Fellow; Program Research Project Grants; Radiation therapy; Research; Research Personnel; Resistance; Role; Signal Transduction; Specificity; Squamous cell carcinoma; T cell response; TNFRSF5 gene; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Toll-like receptors; Training; Tumor Immunity; Tumor-associated macrophages; Up-Regulation; Wild Type Mouse; Work; adaptive immune response; antagonist; antitumor effect; autoinflammatory; cancer cell; carcinogenesis; career; cell type; chemotherapy; combinatorial; cytotoxic; effective therapy; immune activation; immune checkpoint blockade; immune function; immunogenic cell death; immunomodulatory therapies; improved; in vivo; malignant breast neoplasm; microbial; novel; pathogen; patient subsets; programs; radiation response; receptor; recruit; release factor; response; sensor; skills; statistics; targeted treatment; therapeutic target; therapeutically effective; tumor; tumor-immune system interactions; tumorigenesis

PROJECT SUMMARY/ABSTRACT The central theme of my postdoctoral fellowships has been to investigate mechanisms by which myeloid cells are recruited and activated to promote inflammation and immunosuppression during cancer. Chronic inflammation is a recognized hallmark of carcinogenesis and my research focus is to identify critical inflammatory pathways for combinatorial therapeutic strategies, such that the immune system can be harnessed for antitumor immunity. My current research focus is on pancreatic cancer, which is largely resistant to chemotherapy, radiation therapy (RT), and immune checkpoint blockade. RT elicits an immunogenic cell death whereby resident and recruited leukocytes respond to damage-associated molecular patterns (DAMPs) released by dying cells. Macrophages are central mediators of this response and recognize DAMPs via innate adjuvant sensors, including the toll-like receptor (TLR)/MyD88 pathway. Specificity in this pathway is regulated by expression of various NFB subunits that homo- or heterodimerize to drive transcriptional pathways involved in immune activation or immune suppression. My current work is to understand how Mertk-dependent upregulation of NFB p50 regulates macrophage immune suppression post-RT, and suppresses local antitumor immunity by rewiring macrophage response to adjuvant signals through MyD88 signaling. This proposal extends on these findings to test the central hypothesis that inflammasome activation in tumor- associated macrophages restricts RT-induced antitumor CD8+ T cell responses in pancreatic cancer. As the first step of inflammasome activation, MyD88 signaling regulates transcription of IL1 and IL18 while the second step involves additional activation of inflammasome receptors by factors released by dying cells in response to RT. Our preliminary data implicate inflammasome activation in macrophages as a critical mechanism regulating immunosuppression following RT. Thus, we aim to (1) determine the functional significance of inflammasome activation in RT-mediated tumor clearance and (2) identify inflammasome signatures and phenotypes in macrophages responding to RT and determine whether this signature correlates with poor outcomes in patients. Studies utilizing lineage-specific knockout mice will identify the cell types in which inflammasome activation occurs and its functional consequences on regulating CD8+ T cell responses in response to RT. My long-term career goal is to become an independent investigator studying dominant immune mechanisms regulating cancer development and how certain aspects of innate immunity impart barriers to effective therapeutic strategies, including both traditional cytotoxic and immune-based therapies. During the K22 award period I plan to gain additional training to expand my skill set in bioinformatics, statistics, lab management, and communication skills, and to develop my independent research program so that I may establish a record of independent research project grant program funding.

项目摘要/摘要 我博士后研究的中心主题是研究髓系细胞 被招募和激活，以促进癌症期间的炎症和免疫抑制。慢性 炎症是公认的癌症发生的标志，我的研究重点是识别关键的 炎症途径的组合治疗策略，使免疫系统可以 用于抗肿瘤免疫。我目前的研究重点是胰腺癌，这种癌症基本上是耐药的。 化疗、放射治疗(RT)和免疫检查点封锁。RT诱导一种免疫原性细胞 常驻和招募的白细胞对损伤相关的分子模式(DAMP)作出反应的死亡 由垂死的细胞释放。巨噬细胞是这种反应的中心媒介，并通过先天识别湿气 佐剂感受器，包括Toll样受体(TLR)/MyD88通路。这一途径的特异性受到调节 通过表达各种同源或异源二聚体的NFB亚基来驱动转录途径 参与免疫激活或免疫抑制的。我目前的工作是理解MerTK依赖于 NFB p50上调调节RT后巨噬细胞免疫抑制及局部抑制 通过MyD88信号重新连接巨噬细胞对佐剂信号的反应，从而产生抗肿瘤免疫。这 在这些发现的基础上，提出了一项提案，以检验中心假设，即肿瘤中的炎性小体激活- 相关巨噬细胞限制RT诱导的胰腺癌抗肿瘤CD8+T细胞反应。作为 炎症体激活的第一步，MyD88信号调节IL-1和IL-18的转录，而 第二步涉及由死亡细胞释放的因子额外激活炎症体受体。 对RT的响应。我们的初步数据表明巨噬细胞中的炎性小体激活是一个关键因素 RT后免疫抑制的调节机制。因此，我们的目标是(1)确定泛函 炎性小体激活在RT介导的肿瘤清除中的意义及(2)识别炎性小体 巨噬细胞对RT反应的特征和表型，并确定这一特征是否与 患者预后不佳。利用谱系特异性基因敲除小鼠的研究将确定 哪些炎症小体被激活及其对调节CD8+T细胞反应的功能影响 对RT的响应。我的长期职业目标是成为一名研究主导的独立调查员 调节癌症发展的免疫机制以及某些方面的天然免疫如何传递 有效治疗策略的障碍，包括传统的细胞毒性和基于免疫的治疗。 在K22获奖期间，我计划接受额外的培训，以扩大我在生物信息学、统计学、 实验室管理和沟通技能，并开发我的独立研究计划，以便我可以 建立独立研究项目资助计划资金记录。