Metabolic Regulation ofPD-L1 in CD11c+ Cells

CD11c 细胞中 PD-L1 的代谢调节

• 批准号: 10054172
• 负责人: HONG DU
• 金额: $ 53.12万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-04 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054172
• 关键词: Acid Lipase; Amino Acids; Antigen Presentation; Antigen-Presenting Cells; Antigens; Binding; Blood; Bone Marrow; CSF1R gene; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cholesterol; Cholesterol Esters; Clinical Trials; Coculture Techniques; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Environment; Enzymes; FRAP1 gene; Flow Cytometry; Gene Expression Regulation; Generations; Glucose; Glutamine; Goals; Hematopoietic stem cells; ITGAX gene; Immune Cell Suppression; Immunization; Immunosuppression; Immunotherapy; In Vitro; Inflammation; Inflammatory; Injections; Knock-out; Ligands; Lysosomes; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Nonesterified Fatty Acids; Nuclear; Oncogenic; Outcome; PD-1 pathway; PPAR alpha; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Pyruvate; Reactive Oxygen Species; Regimen; Regulation; Role; Signal Transduction; T-Cell Proliferation; T-Lymphocyte; Testing; Triglycerides; Tumor Antigens; Tumor Immunity; Up-Regulation; Wolman Disease; anti-tumor immune response; base; cancer immunotherapy; cancer initiation; cancer therapy; clinical application; design; draining lymph node; effector T cell; experimental study; fatty acid metabolism; immune checkpoint; improved; in vivo; mouse model; neoplastic cell; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; success; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumorigenesis

Project Summary/Abstract The long-term goal is to find better intervening approaches to interdict cancer initiation, progression and metastasis. The PD-L1/PD-1 signaling pathway is a critical immune checkpoint mechanism utilized by tumor to escape antitumor immune responses. PD-L1 binds to PD-1 on activated T cells to mediate an inhibitory signal through PD-1-expressing T cells. In comparison, the functional roles of PD-L1 expression in the myeloid compartment are less clear. CD11c+ DCs are well known for their function to capture tumor antigens and cross-present these antigens to T cells in tumor-draining lymph nodes, resulting in the generation of tumor-specific cytotoxic T lymphocytes (CTLs) that contribute to tumor rejection. Interestingly, we have shown that CD11c+ cells isolated from the blood of lysosomal acid lipase (LAL) knockout (lal-/-) mice possess immunosuppression in the absence of antigen presentation, and directly stimulate tumor proliferation in vitro and tumor growth in vivo. Concomitantly, PD-L1 expression was increased in lal-/- CD11c+ cells, which is required for immunosuppression and tumor stimulation. Our observations suggest that the LAL deficiency-induced metabolic switch leads CD11c+ cells to confer tumor stimulation rather than rejection. Based on these observations, this proposal will focus on how PD-L1 expression in lal-/- CD11c+ cells contributes to immune suppression and tumor stimulation during LAL-deficiency. LAL is a key enzyme that hydrolyzes cholesteryl esters and triglycerides in the lysosome of cells to generate free fatty acids (FFAs) and cholesterol. The metabolites of FFAs are ligands for nuclear transcription factor peroxisome proliferator activated receptor  (PPAR), a negative regulator of inflammation. Since LAL is critically involved in fatty acid metabolism, the proposed study will further elucidate the underneath metabolic mechanism by which lal-/- CD11c+ cells influence tumor immunity and stimulation through PD-L1 expression. RNAseq and flow cytometry demonstrated that PD-L1 expression is regulated by glucose/glutamine metabolic processes and mammalian target of rapamycin (mTOR) in lal-/- CD11c+ cells, which is under the control of PPAR. Therefore, the current proposal will test a central hypothesis that LAL/PPAR/mTOR axis-regulated PD-L1 expression plays a key role in lal-/- CD11c+ cells’ immune suppression and tumor stimulation through metabolic reprogramming. To achieve our goals, we will use the unique lal-/- mouse model and the conditional c-fms-rtTA/(TetO)7-CMV-hLAL;lal-/- triple mouse model (c-fms-Tg/KO) in which hLAL is specifically expressed in the myeloid compartment of lal-/- mice. The following specific aims are designed to test the central hypothesis:1) Characterizing the developmental and metabolic regulation of PD-L1 expression in CD11c+ cells; 2) Characterizing PD-L1 expression of CD11c+ cells in regulating T cell proliferation and functions; 3) Characterizing PD-L1 expression of CD11c+ cells in tumor stimulation. The successful outcome will help to design a more efficient regimen to increase the efficacy of PD-L1 cancer immunotherapy by manipulating the metabolic pathway and the immune checkpoint pathway.

项目总结/文摘