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BLIMP-1 mediated regulation of CD8+ TIL

BLIMP-1 介导的 CD8 TIL 调节

基本信息

批准号：
8439016
负责人：
TIMOTHY N BULLOCK
金额：
$ 30.6万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8439016
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 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

项目摘要

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细胞对其靶点的高度敏感性和特异性为免疫治疗在癌症控制中的应用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。这种功能失调状态的一个主要原因是抑制分子的表达。我们发现，小鼠和人类肿瘤浸润性CD8+细胞毒性T细胞的抑制分子的表达与转录因子BLIMP-1的表达密切相关。在这一应用中，我们发现肿瘤浸润性CD8+T细胞比CD8+T细胞对急性病毒感染的反应过度表达BLIMP-1。我们发现，限制肿瘤浸润性淋巴细胞中BLIMP-1的表达会导致抑制分子表达减少，功能活性增加。此外，我们发现BLIMP-1的表达控制着CD8+T细胞的功能，而不是抑制分子的表达。根据这些数据，我们建议继续进行研究，以确定BLIMP-1在肿瘤浸润性淋巴细胞中的表达是如何调节的，并将确定BLIMP-1的表达如何调节肿瘤浸润性淋巴细胞的功能。这里提出的研究将阐明肿瘤浸润性淋巴细胞功能障碍背后的机制，并将为开发预防功能障碍或恢复功能的干预措施提供机会。活动。