BLIMP-1 mediated regulation of CD8+ TIL

BLIMP-1 介导的 CD8 TIL 调节

• 批准号: 8777888
• 负责人: TIMOTHY N BULLOCK
• 金额: $ 32.62万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777888
• 关键词: Acute; Antibodies; Antigens; Autologous; Blood; CD8B1 gene; Cancer Control; Cancer Vaccines; Cell physiology; Cells; Chronic; Cytotoxic T-Lymphocytes; Data; Development; Diagnostic Neoplasm Staging; Exhibits; Functional disorder; Goals; Human; IL2 gene; Immunotherapy; Indium; Infiltration; Interferons; Intervention; Link; Lymphocyte; Lymphocyte Function; Mediating; Memory; Modeling; Mus; Neoplasm Transplantation; PRDM1 gene; Patients; Play; Production; Regulation; Role; Sensitivity and Specificity; Surface; T-Lymphocyte; Transcription Repressor/Corepressor; Tumor Antigens; Tumor stage; Tumor-Infiltrating Lymphocytes; Virus Diseases; base; cancer immunotherapy; clinically relevant; cytokine; design; functional restoration; functional status; genome-wide; malignant breast neoplasm; melanoma; outcome forecast; pathogen; prevent; promoter; public health relevance; receptor; receptor expression; response; transcription factor; tumor

DESCRIPTION (provided by applicant): The exquisite sensitivity and specificity of T cells for their targets offers considerable promise for the use of immunotherapy in cancer control. However, in many instances, T cells found within tumors are dysfunctional. A major cause for this dysfunctional state is the expression of inhibitory molecules. We have found that the expression of inhibitory molecules by both murine and human tumor infiltrating CD8+ cytotoxic T cells correlates strongly with the expression of the transcription factor BLIMP-1. In this application we show that tumor infiltrating CD8+ T cells over-express BLIMP-1 compared to CD8+ T cells responding to acute viral infection. We show that limiting BLIMP-1 expression in tumor infiltrating lymphocytes results in reduced inhibitory molecule expression and increased functional activity. Further, we show that BLIMP-1 expression controls CD8+ T cell function beyond the expression of inhibitory molecules. From these data, we propose to pursue studies that will define how BLIMP-1 expression is regulated in tumor infiltrating lymphocytes, and will determine how BLIMP-1 expression regulates tumor infiltrating lymphocyte function. The studies presented here will illuminate the mechanisms behind tumor infiltrating lymphocyte dysfunction, and will provide opportunities to develop interventions that either prevent dysfunction, or restore activity.

描述（由申请人提供）：T细胞对其靶标的灵敏度和特异性为在癌症控制中使用免疫疗法提供了相当大的希望。然而，在许多情况下，肿瘤内发现的T细胞功能失调。这种功能障碍状态的主要原因是抑制性分子的表达。我们已经发现，小鼠和人肿瘤浸润性CD 8+细胞毒性T细胞的抑制性分子的表达与转录因子BLIMP-1的表达密切相关。在本申请中，我们表明，与响应急性病毒感染的CD 8 + T细胞相比，肿瘤浸润性CD 8 + T细胞过表达BLIMP-1。我们表明，限制肿瘤浸润淋巴细胞中的BLIMP-1表达导致抑制性分子表达减少和功能活性增加。此外，我们表明，BLIMP-1的表达控制CD 8 + T细胞的功能超出了抑制分子的表达。从这些数据中，我们建议进行研究，以确定如何在肿瘤浸润淋巴细胞中调节BLIMP-1表达，并确定BLIMP-1表达如何调节肿瘤浸润淋巴细胞功能。这里介绍的研究将阐明肿瘤浸润淋巴细胞功能障碍背后的机制，并将提供机会开发干预措施，无论是预防功能障碍，或恢复 活动