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Metabolic Control of Innate and Adaptive Immunity in Breast Cancer

乳腺癌先天性和适应性免疫的代谢控制

基本信息

批准号：
9885847
负责人：
Guangyong Peng
金额：
$ 34.66万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-11 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9885847
关键词：
Address Affect Area Breast Cancer Patient Cancer Etiology Carbon Cell Aging Cell physiology Cells Cellular Metabolic Process Cessation of life Cholesterol Clinical Dendritic Cells Development Energy Metabolism Energy Metabolism Pathway Enzymes Future Glucose Glucose Transporter Glycolysis Goals Human Immune Immune response Immunosuppression Immunotherapy Impairment Investigation Lead Link Lipids Lymphocyte Malignant Neoplasms Mediating Metabolic Metabolic Control Metabolic Diseases Metabolism Molecular Natural Immunity Outcome Outcome Study PD-1/PD-L1 PD-L1 blockade Patients Phenotype Public Health Regulation Regulatory T-Lymphocyte Research Role STAT1 gene STAT3 gene Signal Transduction Source T-Lymphocyte TLR8 gene Testing Tumor Immunity Tumor Suppression Tumor-Derived Tumor-Infiltrating Lymphocytes Woman adaptive immunity advanced breast cancer anti-PD-1 base cancer immunotherapy cancer therapy fatty acid oxidation glucose metabolism glucose transport immune checkpoint blockade immunogenicity immunosenescence improved in vivo lipid metabolism malignant breast neoplasm neoplasm immunotherapy novel novel strategies programmed cell death ligand 1 programmed cell death protein 1 response senescence transcription factor tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Immunotherapy is a promising approach for treating patients with advanced breast cancer. However, immunosuppressive microenvironments induced by regulatory T cells (Treg) present a major barrier to successful anti-tumor immunotherapy. Defining the suppressive mechanisms used by different types of tumor- infiltrating Treg cells is essential for the development of novel strategies to treat human breast cancer. We recently discovered high percentages of  Treg cells existing among the tumor-infiltrating lymphocytes (TILs) of breast tumor patients, which are strongly negatively correlated with clinical outcomes. We further identified a novel suppressive mechanism whereby  Treg cells induce senescence in T cells and dendritic cells (DCs) that then also develop potent suppressive activity. Therefore, it is critical to further identify the molecular mechanisms responsible for  Treg-induced senescence in immune cells, and then to develop strategies to reverse senescence induction mediated by  Treg cells. Increasing evidence indicates that the ability of a lymphocyte to perform functional immune responses is controlled by pathways of energy metabolism. However, little is known about the regulation of energy metabolism in tolerogenic DCs and Treg cells. We recently found that  Treg cells dramatically reprogram DC lipid metabolism. In addition, we observed that TLR8 signaling significantly suppresses glucose metabolism in human  Treg cells via inhibition of both glucose transporters and glycolysis-related enzymes. The central hypotheses of this proposal are that: 1) breast cancer-derived Treg cells rewrite lipid metabolism in DCs, resulting in DC senescence with tolerogenic phenotypes and functions; 2) reprogramming of metabolism in Treg cells and DCs can serve as a novel strategy to synergistically enhance anti-tumor immunity for tumor immunotherapy. Specific Aim 1 seeks to identify what lipid species are changed in  Treg-induced senescent DCs and whether the altered lipid components are causatively related to the DC senescence and impaired functions. We will then investigate the importance of transcription factor STAT and PD1-PDL1 signaling in controlling lipid metabolism disorder, senescence induction and impaired functions occurred in  Treg-treated DCs. Specific Aim 2 will identify the key glucose metabolites that involve  Treg-mediated immune suppression and are regulated by TLR8 signaling for functional reversal in human  Treg cells. We will then test the novel concept that TLR8 activation in  Treg cells combined with checkpoint blockade of PD-L1 in DCs can serve as novel strategies to reprogram their metabolism and synergistically enhance anti-tumor immunity for breast cancer immunotherapy. A positive outcome from these studies should lead to novel strategies to reprogram innate and adaptive immune cell metabolism for future breast cancer immunotherapy.

项目总结/文摘